Objectives: To provide a review of the definition, pathophysiology, differential diagnosis, and treatment of disseminated intravascular coagulation [DIC]. Methods: A case scenario and a review of the literature related to the pertinent facts concerning DIC are provided. Results: DIC is a systemic pathophysiologic process and not a single disease entity, resulting from an overwhelming
activation of coagulation that consumes platelets and coagulation factors and causes microvascular fibrin thrombi, which can result in multiorgan dysfunction syndrome from tissue ischemia. Some conditions associated with acute DIC include septic shock, exsanguinating trauma, burns, or acute promyelocytic leukemia. Conclusions: The massive tissue factor stimulus results in excess intravascular thrombin, which overcomes the anticoagulant systems and leads to thrombosis.
Because of consumption of coagulation factors and platelets, DIC also has a hemorrhagic phase. Treatment of the bleeding patient with DIC is supportive with the use of blood components.
Case History
A 44-year-old man with a medical history of hepatitis C, cirrhosis, and chronic kidney disease sought treatment at the emergency room for altered mental status and an ammonia level over 400 µmol/L [11-51 µmol/L]. The patient was given lactulose; however, his mental status worsened to a point where he required intubation. Vital signs on admission to the intensive care unit [ICU] on October 23 were as follows: blood pressure, 120/84 mm Hg; heart rate, 107 beats/min; respiratory rate, 18/min; and temperature, 97.8°F. The following laboratory results were obtained [reference range is in parentheses] on admission: WBC, 20.1 × 109/L [3.7-10.3 × 109/L]; sodium, 111 mmol/L [136-145 mmol/L]; potassium, 5.7 mmol/L [3.7-4.8 mmol/L]; hemoglobin [Hb], 13.5 g/dL [13.7-17.5 g/dL in males]; platelet count, 253 × 109/L [155-369 × 109/L]; international normalized ratio [INR], 1.4 [0.9-1.2]; prothrombin time [PT], 13.5 seconds [9.6-12.5 seconds]; activated thromboplastin time [aPTT], 34 seconds [19-30 seconds]; and creatinine, 5.8 mg/dL [0.8-1.3 mg/dL]. On October 23, the patient was started on vancomycin, piperacillin/tazobactam, and fluids because of concern for sepsis associated with systemic inflammatory response syndrome and multiorgan failure, as well as laboratory values showing a high WBC count and an elevated lactate of 8 mmol/L [0.5-1.6 mmol/L]. His vital signs worsened over the next 24 hours, and he became hypotensive, requiring treatment with norepinephrine and 6 L of normal saline on October 24. His renal function continued to decline, for which he received continuous renal replacement therapy on October 25. Laboratory values on October 25 were consistent with DIC, showing a significant decrease in hemoglobin, fibrinogen, and platelets and an increase in PT, aPTT, INR, and lactate dehydrogenase [LDH] Table 1. Petechiae were not present. A paracentesis was performed to rule out peritoneal bleeding, and red fluid [shown to be RBCs in the laboratory] was noted on the tap. It was felt that the patient had developed spontaneous multifocal hemoperitoneum secondary to his DIC, and he was given packed RBCs, fresh-frozen plasma, cryoprecipitate, platelets, and vitamin K to treat his peritoneal bleeding, which stopped by October 26. Over the next few days, he continued to require norepinephrine, but eventually his vital signs and laboratory values stabilized. During the next few days, he clinically seemed to improve, but he was found to have multiple infections, including a blood culture growing vancomycin-resistant enterococcus [VRE], a protected alveolar lavage growing Stenotrophomonas maltophilia and VRE, a peritoneal fluid growing Acinetobacter, and a urinalysis growing Candida glabrata. On October 29, he was started on daptomycin, linezolid, trimethoprim/sulfamethoxazole, and fluconazole to treat his current infections, and his vancomycin and piperacillin/tazobactam were discontinued. He remained hemodynamically stable, so he was taken off pressors and extubated on November 1. He was in the process of being transferred out of the ICU, but unfortunately overnight the patient became obtunded and hypotensive. The following laboratory values [reference range] were obtained shortly after midnight on November 4: INR, 2.6 [0.9-1.2]; PT, 25.9 seconds [9.6-12.5 seconds]; aPTT, 44 seconds [19-30 seconds]; Hb, 5.8 g/dL [13.7-17.5 g/dL]; platelet count, 34 × 109/L [155-369 × 109/L]; D-dimer, 8.6 mg/L [160
| Laboratory values [reference range] | ||||||||
| WBC count [3.7-10.3], × 109/L | 20.1 | 10 | 8 | 9 | 6 | 8 | 5-18 | 24.2 |
| Hemoglobin [13.7-17.5], g/dL | 13.5 | 7.7 | 6.7 | 7.7 | 7.9 | 8.1 | 7.5-9.8 | 5.8 |
| Platelet count [155-369], × 109/L | 253 | 81 | 34 | 61 | 67 | 64 | 40-52 | 31 |
| International normalized ratio [0.9-1.2]a | 1.4 | 2 | 2.6 | 1.4 | 1.6 | 1.6 | 1.7-2.1 | 5.9 |
| Prothrombin time [9.6-12.5], sa | 13.5 | 19.4 | 25.9 | 14.2 | 13.9 | 13.9 | 15.8-22 | 36 |
| Activated partial thromboplastin time [19-30], s | 34 | >160 | 41 | 42-49 | >160 | |||
| Fibrinogen [150-450], mg/dL | 66 | 176 | 82 | |||||
| Lactate [0.5-1.6], mmol/L | 8 | 2.0-2.5 | 12 | |||||
| pH [7.35-7.45] | 7.18 | 7.02 | 7.32 | 7.42 | 7.48 | 7.5 | 7.4- 7.45 | 6.77 |
| Lactate dehydrogenase [140-280], U/L | 412 | 262 | 207 | |||||
| Creatinine [0.8-1.30], mg/dL | 5.8 | 6.4 | 2.5 | 1.7 | 1.16 | 1.1 | 1.1-4.0 | 5.24 |
| Blood products, No. | ||||||||
| RBC units | 3 | None | 0 | |||||
| Fresh-frozen plasma units | 2 | 2 | None | 2 | ||||
| Apheresis platelet units | 3 | None | 1 | |||||
| Cryoprecipitate units | 10 | None | 10 |
a
Note that the prothrombin time reagent contains a heparin neutralizer.
Table 1
Summary of Patient Laboratory Data Related to Disseminated Intravascular Coagulation
| Laboratory values [reference range] | ||||||||
| WBC count [3.7-10.3], × 109/L | 20.1 | 10 | 8 | 9 | 6 | 8 | 5-18 | 24.2 |
| Hemoglobin [13.7-17.5], g/dL | 13.5 | 7.7 | 6.7 | 7.7 | 7.9 | 8.1 | 7.5-9.8 | 5.8 |
| Platelet count [155-369], × 109/L | 253 | 81 | 34 | 61 | 67 | 64 | 40-52 | 31 |
| International normalized ratio [0.9-1.2]a | 1.4 | 2 | 2.6 | 1.4 | 1.6 | 1.6 | 1.7-2.1 | 5.9 |
| Prothrombin time [9.6-12.5], sa | 13.5 | 19.4 | 25.9 | 14.2 | 13.9 | 13.9 | 15.8-22 | 36 |
| Activated partial thromboplastin time [19-30], s | 34 | >160 | 41 | 42-49 | >160 | |||
| Fibrinogen [150-450], mg/dL | 66 | 176 | 82 | |||||
| Lactate [0.5-1.6], mmol/L | 8 | 2.0-2.5 | 12 | |||||
| pH [7.35-7.45] | 7.18 | 7.02 | 7.32 | 7.42 | 7.48 | 7.5 | 7.4- 7.45 | 6.77 |
| Lactate dehydrogenase [140-280], U/L | 412 | 262 | 207 | |||||
| Creatinine [0.8-1.30], mg/dL | 5.8 | 6.4 | 2.5 | 1.7 | 1.16 | 1.1 | 1.1-4.0 | 5.24 |
| Blood products, No. | ||||||||
| RBC units | 3 | None | 0 | |||||
| Fresh-frozen plasma units | 2 | 2 | None | 2 | ||||
| Apheresis platelet units | 3 | None | 1 | |||||
| Cryoprecipitate units | 10 | None | 10 |
| Laboratory values [reference range] | ||||||||
| WBC count [3.7-10.3], × 109/L | 20.1 | 10 | 8 | 9 | 6 | 8 | 5-18 | 24.2 |
| Hemoglobin [13.7-17.5], g/dL | 13.5 | 7.7 | 6.7 | 7.7 | 7.9 | 8.1 | 7.5-9.8 | 5.8 |
| Platelet count [155-369], × 109/L | 253 | 81 | 34 | 61 | 67 | 64 | 40-52 | 31 |
| International normalized ratio [0.9-1.2]a | 1.4 | 2 | 2.6 | 1.4 | 1.6 | 1.6 | 1.7-2.1 | 5.9 |
| Prothrombin time [9.6-12.5], sa | 13.5 | 19.4 | 25.9 | 14.2 | 13.9 | 13.9 | 15.8-22 | 36 |
| Activated partial thromboplastin time [19-30], s | 34 | >160 | 41 | 42-49 | >160 | |||
| Fibrinogen [150-450], mg/dL | 66 | 176 | 82 | |||||
| Lactate [0.5-1.6], mmol/L | 8 | 2.0-2.5 | 12 | |||||
| pH [7.35-7.45] | 7.18 | 7.02 | 7.32 | 7.42 | 7.48 | 7.5 | 7.4- 7.45 | 6.77 |
| Lactate dehydrogenase [140-280], U/L | 412 | 262 | 207 | |||||
| Creatinine [0.8-1.30], mg/dL | 5.8 | 6.4 | 2.5 | 1.7 | 1.16 | 1.1 | 1.1-4.0 | 5.24 |
| Blood products, No. | ||||||||
| RBC units | 3 | None | 0 | |||||
| Fresh-frozen plasma units | 2 | 2 | None | 2 | ||||
| Apheresis platelet units | 3 | None | 1 | |||||
| Cryoprecipitate units | 10 | None | 10 |
a
Note that the prothrombin time reagent contains a heparin neutralizer.
Case questions:
How does normal hemostasis occur?
What is the definition of DIC?
How does acute DIC differ from chronic DIC?
What is the pathophysiology of DIC?
What are the conditions predisposing to DIC?
What is the differential diagnosis for DIC?
How is DIC treated?
Normal Hemostasis
To understand DIC, it is best to first review the normal physiology of clot formation. Normal hemostasis is a localized process that results in a primary platelet plug through platelet adhesion and aggregation followed by a secondary fibrin clot through the activation of the coagulation cascade, which occurs in a series of enzymatic steps that lead to the formation of thrombin. Thrombin then converts soluble fibrinogen to an insoluble clot of fibrin polymers, which forms a mesh that incorporates the previously formed platelet plug as well as RBCs, if present. Traditionally, this secondary hemostasis coagulation cascade was thought to be initiated either through tissue factor [TF] release into the bloodstream, which activates factor VII and then the extrinsic system, or through disruption of the endothelium exposing collagen and the subendothelium directly to blood. This results in platelet aggregation, which in the past was thought to activate factor XII in vivo and subsequently the rest of the intrinsic [contact] cascade Figure 1.
Figure 1
The coagulation cascade showing coagulation factor activation in plasma: intrinsic, extrinsic, and common pathways. a, activated factor; HMWK, high molecular weight kininogen; II, prothrombin; IIa, thrombin; K, kallikrein; PK, prekallikrein; TF, tissue factor.
Today, it is thought that in vivo secondary hemostasis takes place mainly through TF activation of the cell-based system, even where there is breakdown of the endothelium.1 Here, TF, considered to be part of most cell membrane lipoproteins, is either released upon damage of a cell, including the endothelial cells, or secreted into the blood by platelets and/or monocytes after stimulation. Factor VII is then activated, and through a series of enzyme reactions proceeding on cell membranes involving the activation of several coagulation factors [X, IX, XI, and prothrombin], thrombin is formed and subsequently a fibrin clot. Factors V and VIII are nonenzyme catalysts in this model, and factor XII is not part of this new coagulation in vivo system. The major roles of the contact system [factor XII, high molecular weight kininogen [HMWK], and prekallikrein [PK]] are to enhance the inflammatory response by stimulating chemotaxis in neutrophils and activating C1, C3, and C5 in the complement system and to promote vascular repair. HMWK can be enzymatically altered by factor XIIa, factor XIa, and/or kallikrein to produce bradykinin, a vasoactive agent causing vascular dilation, increased vascular permeability [as seen in inflammation], and endothelial cells to release tissue plasminogen activator [TPA]. Therefore, the activation of factor XII in vivo is thought to be primarily associated with inflammation and vascular repair rather than coagulation. On the other hand, in the test tube [in vitro], the plasma-based coagulation test, aPTT, will be very prolonged if there is a deficiency of factor XII. Factor XII is needed in the first step [contact] of the intrinsic coagulation pathway in vitro but is thought to play a minor role, if any, in normal physiologic clot formation in vivo. However, because of prevention of pathologic thrombus formation in factor XII–deficient mice, factor XII may play a role in the pathologic propagation and stabilization of fibrin thrombi in ischemic strokes and pulmonary emboli.2 Factor XII inhibition is under investigation as a possible anticoagulant therapy that would not increase the risk of bleeding.3
Once a fibrin clot is produced, it is stabilized by covalent cross-linking through the actions of factor XIII. The last step of the healing process is for blood clots to be reorganized and resorbed by fibrinolysis so that unimpeded blood flow through the originally damaged vessel can be reestablished. The plasma protein plasminogen, the inactive precursor to the active fibrinolysis agent plasmin, is bound to fibrinogen and fibrin so that it is incorporated into clots. When endothelial cells are injured, they release TPA, which causes the plasminogen in clots to convert to plasmin and digest the cross-linked fibrin clot to form soluble fibrin degradation products. Any free circulating plasmin is rapidly inactivated by plasma α2-antiplasmin, made in the liver, and plasminogen activator inhibitor 1 [PAI-1], from endothelial cells, inhibits TPA activity.1
There is a generalized interrelationship between the initiation of coagulation, complement activation, and the inflammatory response, so that when one is activated, the others are stimulated as well Figure 2. They interact through a mechanism known as “crosstalk,” as shown in Figure 3.4
Figure 2
Generalized interrelationship between the initiation of coagulation, complement activation, and the inflammatory response.
Figure 3
Crosstalk between coagulation, complement activation, and inflammation. Modified from Kurosawa S and Stearns-Kurosawa DJ.4 a, activated factor; DAMPS, damage-associated molecular patterns; PAMPS, pathogen-associated molecular patterns.
Essentially, primary hemostasis [platelet aggregation] stimulates secondary hemostasis [the coagulation factor cascade] through TF/factor VIIa as well as inflammation through the factor XIIa/kallikrein/bradykinin/C3a mechanism.4 Complement can then lyse cells and/or bacteria, which release damage-associated molecular patterns [DAMPs] and/or pathogen-associated molecular patterns [PAMPs] as well as phospholipids, which all can stimulate secondary hemostasis. DAMPs are warning signals that cell damage has occurred, and DAMP receptors, when activated, cause cellular signaling pathways to initiate physiologic actions resulting in damage containment and repair, which include inflammatory, immune, and coagulation responses. A subset of DAMPs is PAMPs consisting of microbial molecules that alert multicellular animals to the presence of invading organisms. PAMPs are detected by the immune system through Toll-like receptors, which activate signaling cellular pathways, creating both an inflammatory and an immune response. The immune response produces specific antibodies and specific T cells to destroy the intruding pathogens while the inflammatory response is more general in nature.5 Both thrombin and plasmin can stimulate C5a to create more cell lysis.
DIC
Definition and Background
In 2001, the International Society on Thrombosis and Hemostasis [ISTH] proposed a definition of DIC that included microvascular thrombosis: “DIC is an acquired syndrome characterized by the intravascular activation of coagulation without a specific localization and arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction.”6
In response to an injury to the blood vessel wall, clotting occurs only as a localized phenomenon, as part of normal healing, because there are many checks and balances to prevent extension of the hemostatic plug mechanism to the whole intravascular system. The pathophysiology of DIC, in simple terms, is that the underlying disease stimulates such a strong procoagulant activity that it results in an excess of thrombin, which then overcomes the anticoagulant control mechanisms of protein C [PrC], antithrombin [AT], and the tissue factor pathway inhibitor [TFPI], allowing thrombosis to freely take place throughout the vasculature.1 In DIC, there is a battle between the excess thrombin state, which clinically manifests itself as thrombosis, embolism, and microvascular occlusion by fibrin thrombi, leading to multiorgan dysfunction syndrome [MODS] from tissue ischemia, and a hemorrhagic disorder from depletion of platelets, consumption of coagulation factors, and/or accelerated plasmin formation.7 Both thrombosis and bleeding can be present in the same patient. DIC is a manifestation/symptom/sign of an underlying pathologic process, as is fever, and is not a specific disease entity. If the causative disease or condition is successfully treated, the DIC will disappear.
Laboratory abnormalities in this “consumption coagulopathy” include prolonged aPTT and PT/INR, a decrease in platelet count and in fibrinogen, and an increase in fibrin degradation products, including D-dimers [plasmin degradation of cross-linked fibrin].
In the older literature, DIC was also known as defibrination syndrome, acquired afibrinogenemia, consumptive coagulopathy, and thrombohemorrhagic disorder.1
Maladies resulting in both thrombosis and hemorrhage have been recognized for centuries, the foremost of which were the “black plague” of the Middle Ages with symptoms of gangrene of the fingers as well as generalized hemorrhage in organs. It remains controversial as to whether the cause of this plague was from Yersinia pestis, spread by the bites of the rat flea, or from an Ebola-like hemorrhagic virus.8
DIC was first experimentally induced by M. Dupuy in 1834 when he intravenously injected brain tissue into animals, resulting in clots seen throughout the vasculature. In 1873, B. Naunyn intravenously injected dissolved RBCs and observed disseminated thrombosis. A. Trousseau in 1865 described in patients with advanced malignancy, the multiple thromboses, and tendency of blood to clot. In 1961, Lasch et al introduced the concept of consumption coagulopathy as the mechanism leading to hemorrhage in DIC.1
DIC is relatively uncommon in the general hospitalized patient but accounts for 9% to 19% of ICU admissions and has a high mortality rate of 45% to 78%.9
Acute vs Chronic DIC
Acute DIC is a consumption coagulopathy state where excess thrombin is generated to such a high degree that it overcomes the large amounts of natural anticoagulants normally present in the plasma.10 Acute DIC is usually triggered by large amounts of tissue factor released into the intravascular space, leading to generalized deposition of fibrin thrombi in the microvasculature contributing to multiorgan dysfunction.10,11 MODS most frequently involves the lungs and kidneys followed by brain, heart, liver, spleen, adrenals, pancreas, and the gastrointestinal [GI] tract.10
Thrombin has the following general procoagulant actions12 [see Figure 1]:
Converts fibrinogen to fibrin
Activates factors V, VIII, and XI to stimulate further thrombin formation
Activates factor XIII to stimulate fibrin cross-linking
Causes platelet aggregation, which induces the coagulation cascade system to generate even more thrombin
These actions of thrombin cause more activation of coagulation factors, resulting in the production of more thrombin and therefore more fibrin clot. This ultimately leads to fibrinolysis, in which fibrin thrombi are broken down by plasmin with the subsequent release of fibrin degradation products [FDPs]. When intravascular, these FDPs can inhibit fibrin polymerization as well as platelet aggregation by interfering with the GPIIbIIIa fibrinogen receptor.7 These FDPs, in concert with the consumption of platelets, fibrinogen, and coagulation factors, contribute to the most common symptom seen in acute DIC: bleeding.
Other thrombin-induced situations enhance clot formation activities in DIC. Thrombin proteolytically cleaves a class of extracellular G-protein-coupled receptors on the platelet called protease-activated receptors [PARS], which then converts the stimulus into intracellular signaling events that include release of interleukins [ILs]: IL-1 and IL-6. This leads to proinflammatory activity with an increase in platelet activation and leukocyte adhesion.13 Thrombin causes release of PAI-1 from endothelial cells and activates thrombin-activatable fibrinolysis inhibitor [TAFI] in the plasma, both of which impair plasminogen activation, thereby reducing clot dissolution from plasmin. In addition, DIC causes the consumption of AT and the downregulation of the PrC system, diminishing the ability of the body to turn thrombin off. AT production can be diminished as a consequence of hepatic MODS and can be degraded by enzymes released from neutrophils. TFPI may also be reduced in DIC.
Shock often occurs in DIC and can lead to impaired clearance of tissue factor, activated coagulation factors, and FDP by the reticuloendothelial system macrophages of the spleen and liver, thereby perpetuating the DIC.7 Shock could be caused by the excessive stimulation of the contact system [factor XII, HMWK, and PK], resulting in large amounts of bradykinin production, which cannot be inhibited by the presence of normal concentrations of angiotensin-converting enzyme. Shock is probably responsible for the hyperfibrinolysis syndrome by endothelial cell release of TPA from and the amplification of the PrC system when there is hypoperfusion of endothelial cells. In many situations, the hyperfibrinolysis syndrome occurs in the later stages of DIC, but in acute traumatic coagulopathy, hyperfibrinolysis usually occurs in the early phase of trauma, giving rise to hypercoagulability in the later phases because of sustained increase in PAI-1.14
Acute DIC results in rapid consumption of platelets and coagulation factors so that at the time of diagnosis, the platelet count may be less than 50,000/μL [10%-15% of cases], the PT and aPTT may be extremely prolonged, and the D-dimers are high.10,15 However, it is important to keep in mind that the aPTT and, less often, the PT may be minimally prolonged. The platelet-poor plasma tests, PT and aPTT, both reflect the level of factors in the common pathway of coagulation: factors X, V, and II [prothrombin] and fibrinogen [see Figure 1]. This is the pathway “common” to both the extrinsic and intrinsic systems that result in the activation of thrombin and conversion of fibrinogen to fibrin. In addition, the PT reflects the level of factor VII in the extrinsic pathway. In this pathway, factor VII is activated by tissue factor, which then proceeds through the common pathway, leading to activation of thrombin and fibrin clot formation. In addition, the aPTT measures the intrinsic pathway, which includes factors XII, XI, IX, and VIII. In this pathway, factor XII is activated by collagen or polyphosphate, which eventually leads to the activation of the common pathway and fibrin clot formation. The PT and aPTT are both prolonged in DIC because they contain coagulation factors that have been consumed: factor V, factor VIII, and fibrinogen.
In acute DIC, thrombin’s activity is also enhanced because of the decrease in antithrombin from [1] consumption of AT, [2] degradation of AT from the release of neutrophil elastase, and [3] decreased production of AT by the liver because of microvascular thrombosis. In addition, the PrC pathway of thrombin inactivation is diminished by down-regulation of thrombomodulin by the proinflammatory cytokines tumor necrosis factor α, IL-1, and IL-6 as well as by a decrease in free protein S secondary to protein S being bound to the increased complement C4b-binding protein, an acute phase reactant.1 The proinflammatory cytokines induce endothelial cells to release PAI-1. The capillary endothelial cell is the mediator for the bidirectional crosstalk between the coagulation and inflammatory systems.13
D-dimers are a specific type of fibrin degradation product consisting of polymerized fibrin monomers that have been cross-linked by activated factor XIII and subsequently cleaved by plasmin.15 Hence, D-dimers are only produced when three enzymes are functioning: thrombin, factor XIIIa, and plasmin. D-dimers are therefore created after intravascular coagulation and clot formation have recently occurred. D-dimers are increased in a number of conditions in which clot formation occurs, including arterial or venous thrombosis, preeclampsia, eclampsia, and DIC. However, D-dimers may also be produced during extravascular coagulation and clot formation and are commonly elevated in hospitalized patients without overt intravascular thrombosis. Such scenarios include trauma, surgery, healing, and inflammation. Elevated levels of D-dimers may also be seen in severe liver disease due to decreased clearance of the D-dimers. The absence of D-dimers is especially useful as a negative predictive tool to exclude a diagnosis of DIC. Elevated levels are useful in helping confirm an already suspected diagnosis of DIC.
Chronic DIC may develop when the body is exposed to smaller amounts of thrombin for prolonged periods [ie, malignancy, metastasis, intrauterine fetal death, vasculitis, aneurysms, hemangiomas, and large areas of healing such as a thigh or retroperitoneal hematoma].10 While coagulation factors and platelets are consumed, it is not as brisk as that seen in acute DIC, and the body is able to partially compensate through increased production of coagulation factors, platelets, antithrombin, and antiplasmin. In addition, FDPs are still efficiently cleared by the liver. Therefore, thrombosis typically dominates bleeding in chronic DIC, and shock is often not present in this setting. In fact, there may be no symptoms, and the PT and aPTT may be only slightly prolonged or normal, making the laboratory diagnosis of DIC confusing. The platelet count is typically only mildly decreased in chronic DIC.
Acute DIC is initially a hypercoagulable state where fibrin thrombi are formed in arterioles and capillaries, often resulting in ischemia and multiorgan failure. As RBCs are pushed through these compromised tiny vessels in the microvasculature, they become fragmented to form schistocytes [broken RBCs; Image 1], resulting in microangiopathic hemolytic anemia [MAHA]. Acute DIC is therefore a thrombotic MAHA because there is thrombocytopenia in addition to schistocyte formation. The free hemoglobin released in this hemolytic process enhances the hypercoagulable state by combining with nitric oxide [endothelial relaxing factor]. The removal of intravascular nitric oxide by free hemoglobin can cause vasospasm and platelet activation. Other abnormal tests in acute DIC are related to hemolysis and include increased serum LDH and hyperbilirubinemia.
Image 1
Schistocytes on peripheral blood smear ×100. Up to three schistocytes per high-power field is normal. Arrows show more than 10 schistocytes per high-power field. Picture taken with oil emersion lens at ×100.
The major conditions associated with acute DIC can be seen in Table 2. Clinical manifestations of acute DIC can present in many ways, but the most common are petechia/purpura, altered mental status, general malaise, internal organ and/or mucosal/skin bleeding, and hypotension. The diagnosis of DIC is made through a constellation of factors, including medical history, general signs and symptoms, and laboratory tests. There is no single test to diagnose DIC. See Table 3 for coagulation-related laboratory test results in DIC.
Table 2
Major Conditions Often Associated With Acute Disseminated Intravascular Coagulation
| Infection—gram-negative septic shock, Rickettsia [ticks], gram-positive bacteria, fungi, viruses, malaria |
| ABO-incompatible transfusion reaction |
| Acute pancreatitis |
| Septic abortion, amniotic fluid embolism |
| Acute promyelocytic leukemia |
| Brain injury |
| Trauma and crush injury |
| Burns |
| Hypothermia/hyperthermia |
| Fat emboli |
| Vascular tumors |
| Snake bite venom |
| Transplant rejection |
| Infection—gram-negative septic shock, Rickettsia [ticks], gram-positive bacteria, fungi, viruses, malaria |
| ABO-incompatible transfusion reaction |
| Acute pancreatitis |
| Septic abortion, amniotic fluid embolism |
| Acute promyelocytic leukemia |
| Brain injury |
| Trauma and crush injury |
| Burns |
| Hypothermia/hyperthermia |
| Fat emboli |
| Vascular tumors |
| Snake bite venom |
| Transplant rejection |
Table 2
Major Conditions Often Associated With Acute Disseminated Intravascular Coagulation
| Infection—gram-negative septic shock, Rickettsia [ticks], gram-positive bacteria, fungi, viruses, malaria |
| ABO-incompatible transfusion reaction |
| Acute pancreatitis |
| Septic abortion, amniotic fluid embolism |
| Acute promyelocytic leukemia |
| Brain injury |
| Trauma and crush injury |
| Burns |
| Hypothermia/hyperthermia |
| Fat emboli |
| Vascular tumors |
| Snake bite venom |
| Transplant rejection |
| Infection—gram-negative septic shock, Rickettsia [ticks], gram-positive bacteria, fungi, viruses, malaria |
| ABO-incompatible transfusion reaction |
| Acute pancreatitis |
| Septic abortion, amniotic fluid embolism |
| Acute promyelocytic leukemia |
| Brain injury |
| Trauma and crush injury |
| Burns |
| Hypothermia/hyperthermia |
| Fat emboli |
| Vascular tumors |
| Snake bite venom |
| Transplant rejection |
Table 3
Coagulation-Related Laboratory Results in DICa
| Platelet count | Decreased—consumed |
| Activated partial thromboplastin time | Prolonged |
| Prothrombin time | Prolonged |
| Thrombin time | Prolonged—due to low fibrinogen and elevated D-dimer |
| Fibrinogen | Decreased—consumed |
| Coagulation factors | Decreased—consumed |
| Fibrin degradation products | Increased |
| D-dimer | Increased |
| Thrombin generation markers | Increased |
| Antithrombin | Decreased—consumed |
| Protein C | Decreased—consumed |
| Protein S | Decreased—consumed |
| Thrombomodulin, endothelial | Decreased by neutrophil elastase + proinflammatory cytokines |
| TPA trauma | Early DIC—increased Late DIC—decreased |
| PAI-1 trauma | Early DIC—low levels Late DIC—elevated |
| Platelet count | Decreased—consumed |
| Activated partial thromboplastin time | Prolonged |
| Prothrombin time | Prolonged |
| Thrombin time | Prolonged—due to low fibrinogen and elevated D-dimer |
| Fibrinogen | Decreased—consumed |
| Coagulation factors | Decreased—consumed |
| Fibrin degradation products | Increased |
| D-dimer | Increased |
| Thrombin generation markers | Increased |
| Antithrombin | Decreased—consumed |
| Protein C | Decreased—consumed |
| Protein S | Decreased—consumed |
| Thrombomodulin, endothelial | Decreased by neutrophil elastase + proinflammatory cytokines |
| TPA trauma | Early DIC—increased Late DIC—decreased |
| PAI-1 trauma | Early DIC—low levels Late DIC—elevated |
DIC, disseminated intravascular coagulation; PAI-1, plasminogen activator inhibitor 1; TPA, tissue plasminogen activator.
a
Typically, the only coagulation laboratory tests routinely performed to evaluate for DIC are platelet count, prothrombin time, Activated partial thromboplastin time, fibrinogen, and D-dimer.
Table 3
Coagulation-Related Laboratory Results in DICa
| Platelet count | Decreased—consumed |
| Activated partial thromboplastin time | Prolonged |
| Prothrombin time | Prolonged |
| Thrombin time | Prolonged—due to low fibrinogen and elevated D-dimer |
| Fibrinogen | Decreased—consumed |
| Coagulation factors | Decreased—consumed |
| Fibrin degradation products | Increased |
| D-dimer | Increased |
| Thrombin generation markers | Increased |
| Antithrombin | Decreased—consumed |
| Protein C | Decreased—consumed |
| Protein S | Decreased—consumed |
| Thrombomodulin, endothelial | Decreased by neutrophil elastase + proinflammatory cytokines |
| TPA trauma | Early DIC—increased Late DIC—decreased |
| PAI-1 trauma | Early DIC—low levels Late DIC—elevated |
| Platelet count | Decreased—consumed |
| Activated partial thromboplastin time | Prolonged |
| Prothrombin time | Prolonged |
| Thrombin time | Prolonged—due to low fibrinogen and elevated D-dimer |
| Fibrinogen | Decreased—consumed |
| Coagulation factors | Decreased—consumed |
| Fibrin degradation products | Increased |
| D-dimer | Increased |
| Thrombin generation markers | Increased |
| Antithrombin | Decreased—consumed |
| Protein C | Decreased—consumed |
| Protein S | Decreased—consumed |
| Thrombomodulin, endothelial | Decreased by neutrophil elastase + proinflammatory cytokines |
| TPA trauma | Early DIC—increased Late DIC—decreased |
| PAI-1 trauma | Early DIC—low levels Late DIC—elevated |
DIC, disseminated intravascular coagulation; PAI-1, plasminogen activator inhibitor 1; TPA, tissue plasminogen activator.
a
Typically, the only coagulation laboratory tests routinely performed to evaluate for DIC are platelet count, prothrombin time, Activated partial thromboplastin time, fibrinogen, and D-dimer.
For those clinicians not experienced in making the diagnosis of DIC, there are two popular algorithms available to help. The ISTH has a DIC scoring system related to whether there is an underlying disorder known to cause DIC, the degree of thrombocytopenia, the level of fibrinogen, the level of PT prolongation, and whether there are elevated fibrin-related markers.6
The proposed acute DIC diagnostic algorithm by the Scientific Subcommittee on DIC of the ISTH is seen in Table 4.6 This algorithm requires that the patient has a disease known to be associated with DIC and uses common coagulation tests. This ISTH DIC algorithm has been shown to be 93% sensitive and 97% specific for the diagnosis of overt [acute] DIC.16
Table 4
Acute DIC Algorithm Proposed by the International Society on Thrombosis and Haemostasisa
| 1. Presence of an underlying disorder known to be associated with DIC? | |
| If yes: proceed. If no: do not use this algorithm | |
| 2. Global coagulation results: | |
a. Platelet count [>100,000/μL = 0, 1.0 g/L = 0; 100,000/μL = 0, 1.0 g/L = 0; 100,000/μL = 0, 1.0 g/L = 0; 100,000/μL = 0, 1.0 g/L = 0;
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