DIC is a secondary disorder that occurs as a result of tissue injury, inflammation, or abnormal regulatory mechanisms (Fig. 11.1) (Mercer et al., 2006; Toh & Downey, 2005; Geiter, 2003; Messmore & Wehrmacher, 2002; Levi & de Jonge, 2000). Inflammatory cytokines thought to contribute to the development of DIC include tumor necrosis factor and interleukin-6 (Furlong & Furlong, 2005; Levi & de Jonge, 2000). Endothelial injury activates monocytes and endothelial cells, causing them to produce and express tissue factor that stimulates thrombin (Toh & Downey, 2005; Messmore & Wehrmacher, 2002).
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| Fig. 11.1Pathophysiology of DIC.(Data from Hambleton, J., Leung, L. L., & Levi, M. (2002). Coagulation: Consultative hemostasis. Hematology, 1:335–352; Levi, M. (2005). Disseminated intravascular coagulation. Critical Care Clinics, 21:449–467; Messmore, H. L., & Wehrmacher, W. H. (2002). Disseminated intravascular coagulation: A primer for primary care physicians. Postgraduate Medicine, 111(3). Retrieved August 3, 2007, from http://www.postgradmed.com/issues/2002/03_02/messmore.htm.) |
The International Society on Thrombosis and Haemostasis defines DIC as “[an] acquired syndrome characterized by the intravascular activation of coagulation with loss of localization arising from different causes. It can originate from and cause damage to the microvasculature sufficiently severe to produce organ dysfunction” (Angstwurm et al., 2006; Voves et al., 2006; Taylor et al., 2001). DIC is also known as consumption coagulopathy and defibrination syndrome (Kanwar et al., 2006; Leung, 2006a).
The clinical stimulus for DIC originally was thought to be multifactorial. The disorder now is known to be caused almost exclusively by extrinsic factor (Factor VII, tissue factor, tissue plasminogen activator) (Mercer et al., 2006; Leung, 2006b; Toh & Downey, 2005; Levi & de Jonge, 2000).
Increased thrombin generation leads to widespread intravascular deposition of this protein, causing thrombotic occlusion of midsize and small vessels (Leung, 2006b).
Impairment of mechanisms to prevent coagulation and inadequate fibrinolysis exacerbate the thrombotic process. Normal anticoagulant regulatory processes, such as tissue factor platelet inhibitor (TFPI), antithrombin III, and activated protein C, are impaired (Mercer et al., 2006; Furlong & Furlong, 2005).
Simultaneous use and subsequent depletion of platelets and clotting factors, as a consequence of the ongoing coagulation, may result in thrombocytopenia, reduced fibrinogen levels, and severe bleeding (Leung, 2006b).
Most patients have thromboses, and a minority of patients have acute hemorrhage despite thrombocytopenia (Hambleton et al., 2002).
The pathophysiology of cancer-related DIC may have some unique characteristics. Solid tumor malignancies can express tumor-associated procoagulants, such as cancer procoagulant (CP) (Kanwar et al., 2006; Leung, 2006a; Hambleton et al., 2002).Tumors are major stimulants of tissue injury and the extrinsic pathway, making them one of the major causes of both acute and chronic DIC. Because the brain contains large amounts of tissue factor, DIC and other procoagulant activity are common in patients with primary brain tumors, brain metastases, or brain injury and in those who have had brain surgery.
EPIDEMIOLOGY AND ETIOLOGY
The incidence of DIC likely is underreported because of its similarity to bleeding arising from other causes. The incidence in hospitalized adults is reported to be 1% (Leung, 2006a). In a study of hospitalized children, the overall incidence was 1.12% (Oren et al., 2005). The incidence of DIC in sepsis is thought to exceed 30% to 50%, but other coagulopathic abnormalities make concrete diagnosis of this disorder difficult (Furlong & Furlong, 2005). Patients with cancer have clearly identifiable tissue injury stimuli, and the reported incidence of DIC in patients with solid tumors or hematologic malignancies is 10% to 15% (Leung, 2006b).
RISK PROFILE
The most common etiology of DIC is sepsis (Duran & Tannock, 2006; Leung, 2006b; Oren et al., 2005; Hambleton et al., 2002).
• Although DIC has been associated with all microbes (bacteria, fungi, protozoa, and viruses), bacteria are the most common etiologic organisms (Leung, 2006b), and of these, gram-negative bacteria are the most common causes.
• Specific organisms with a pronounced risk for causing DIC include meningococci, Staphylococcus aureus, Streptococcus pneumoniae, and Clostridium perfringens (Kanwar et al., 2006; Leung, 2006b).
• Factors that accentuate the DIC pathophysiologic process include endotoxin damage to the endothelium, shock-induced tissue damage, and impaired hepatic perfusion that impedes clearance of activated clotting proteins (Leung, 2006b).
Severe tissue injury that stimulates widespread clotting by means of activation of Factor VII or the release of tissue material is the second most common cause of DIC in the following patient populations (Duran & Tannock, 2006; Hambleton et al., 2002):
• Traumatic injury (particularly brain injury that results in high levels of tissue factor [Leung, 2006b])
• Burns
• Major surgeryj
• Renal failure
• Severe pancreatitis (Toh & Downey, 2005)
Obstetric complications can be a factor in the development of DIC. The presence of the “foreign” fetus has been known to trigger inflammatory and immunologic processes, causing autodestruction of tissue. Leakage of a thromboplastin-like substance from the placenta is another proposed mechanism by which obstetric disorders cause DIC (Hambleton et al., 2002). Eclampsia and hemolytic syndrome are inflammatory processes, and placenta abruptio causes life-threatening hemorrhage.
Solid tumor malignancies provide a constant level of tissue injury, triggering abnormal clotting stimuli. They have long been associated with the development of DIC and are the third most common cause of this disorder (Duran & Tannock, 2006; Schlaeppi et al., 2006; Levi, 2001; Sallah et al., 2001).
• Approximately 10% to 15% of all patients with metastatic solid tumor malignancies have evidence of DIC (Duran & Tannock, 2006).
• Prostate cancer has been reported with greater predominance than many other tumors. The theory is that the prostate is rich in urokinase, which is released when this organ is injured, resulting in tissue injury and microvascular hemorrhage.
• Metastatic malignant melanoma has been associated with extensive soft tissue injury and release of tissue thromboplastin (Schlaeppi et al., 2006).
Hematologic malignancies can be a catalyst for DIC.
• Both at diagnosis and after treatment, as many as 15% of patients with acute leukemia show abnormal results on coagulation laboratory tests that are indicative of DIC (Duran & Tannock, 2006). For many of these patients, DIC remains subclinical; however, it is still an omnipresent, serious risk for thrombosis, bleeding, or multiorgan failure (Barbui & Falanga, 2001; Chojnowski et al., 1999).
• Patients with leukemia or lymphoma and high fibrinogen levels have a poorer prognosis than those with low fibrinogen levels (Wada et al., 2003).
• Acute myelogenous leukemia, M3 subtype (acute progranulocytic leukemia [APL]) is the most common hematologic malignancy to present with DIC. The less differentiated progranulocytes contain granules filled with procoagulants, which cause excessive clotting when undergoing lysis (Yanada et al., 2006; Barbui & Falanga, 2001).
• Acute lymphoblastic leukemia, B cell subtype, when associated with a high bone marrow blast count (Smith et al., 2006) is a catalyst for DIC.
Hemoglobinemia or hemoglobinuria caused by hemolysis can cause DIC.
• Primary hematologic disorders that cause hemolysis, such as paroxysmal nocturnal hemoglobinuria (PNH), can give rise to DIC (Furlong & Furlong, 2005).
• Intravenous immunoglobulin (anti-D IVIg) used to treat immune thrombocytopenia purpura has been reported to cause fatal DIC (Gaines, 2005).
• Vascular necrosing disorders, such as giant hemangioma, can cause DIC (Furlong & Furlong, 2005).
Vascular disorders (e.g., vasculitis, major vascular trauma, large vascular aneurysms, and giant hemangiomas) can cause local inflammation and activation of coagulation (Hambleton et al., 2002).
Toxic or immunologic reactions can cause DIC, such as snakebite, recreational drug use, transfusion reactions, organ transplant rejection, exacerbation of autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis), tuberculosis, osteomyelitis, heat stroke, and amphetamine overdose (Kanwar et al., 2006; Leung, 2006b; Furlong & Furlong, 2005; Hambleton et al., 2002; Messmore & Wehrmacher, 2002).
PROGNOSIS
The syndrome of disseminated intravascular coagulation may present in an acute and fulminant state, for which the prognosis for full recovery is unlikely but survival is approximately 50%. Factors associated with a poor outcome include advanced age, severity of underlying disease, and severity of hemostatic abnormalities (Leung, 2006a). The most important prognostic variable is the ability to correct the underlying disorder (Kanwar et al., 2006; Leung, 2006a); meningococcal infection, for example, has an extremely high mortality rate (60% to 80%) (Leung, 2006a).
In children, DIC frequently is associated with sepsis and organ failure, bleeding rather than thrombosis, and a mortality rate over 75% (Oren et al., 2005; Vincent & De Backer, 2005).
Chronic DIC occurs with a persistent, low-level coagulation stimulus, such as the presence of a tumor in the abdomen. The clotting stimulus produces abnormal thromboses, exemplified by hypercoagulability and a high risk for clotting complications such as pulmonary emboli or upper extremity thromboses. However, the patient does not have the rapid, uncontrolled hemorrhage seen in the acute form of DIC (Leung, 2006b; Messmore & Wehrmacher, 2002).
DIC is an independent predictor of mortality in patients with sepsis or severe trauma (Sivula et al., 2005; Hambleton et al., 2002).
PROFESSIONAL ASSESSMENT CRITERIA (PAC)
1. Thromboses in the microvasculature are early and common clinical findings. It is generally accepted that thromboses are manifested as organ failure (Mercer et al., 2006; Vincent & De Backer, 2005).
2. Hemorrhage, initially from small vessels but later more globally, manifests as the coagulation factors are depleted by microcirculatory clotting. Initial bleeding is mucosal and also is seen around intravenous lines or from wounds and skin injuries. As the disorder progresses, bleeding from larger vessels becomes evident.
3. Intracranial hemorrhage is the most common cause of early mortality in DIC, followed by multiorgan failure (Leung, 2006a).
4. Purpura fulminans is a condition of severe, subcutaneous hemorrhagic lesions that spread and are most often associated with a sepsis etiology (Kanwar et al., 2006). These patients have a higher risk for mortality (Furlong & Furlong, 2005).
5. DIC may present with a wide range of clinical findings (Table 11-1). The acute and fulminant form of the disorder (referred to as bleeding DIC), in which activation of fibrinolysis is the predominant feature, is well known in the critical care area. Bleeding DIC is more likely to be related to sepsis or obstetric complications, tissue injury, and acute progranulocytic leukemia (Duran & Tannock, 2006). Chronic, or low-grade, DIC is more common in patients with mild to moderate continuous tissue injury, such as those with mucin-producing tumors (e.g., adenocarcinoma).
| Body System | Thrombotic Symptoms/Complications | Hemorrhagic Symptoms/Complications |
|---|---|---|
| Neurologic/sensory | Confusion/disorientation Ischemic stroke | Unilateral weakness, papillary changes Intracranial hemorrhage |
| Respiratory | Persistent dry cough Pulmonary emboli | Alveolar hemorrhage Hemoptysis Pleural effusion/hemothorax |
| Cardiovascular | Myocardial infarction Trousseau’s syndrome (superficial migratory thrombophlebitis) Nonbacterial thrombotic endocarditis | Pericardial effusion |
| Renal | Acute renal failure Oliguria | Hematuria |
| Gastrointestinal | Bowel infarction Jaundice from hepatic obstruction | Gastrointestinal hemorrhage (hematochezia, hematemesis, melena) |
| Musculoskeletal | Joint pain Severe muscle pain | Joint swelling and limited motion Swollen, hard muscle/compartment syndrome |
| Integumentary/mucosal | Acral cyanosis Skin necrosis of limbs | Ecchymoses Epistaxis Gangrene Gingival bleeding Hemorrhagic bullae Petechiae Wound bleeding |
| Endocrine | Adrenal infarction/insufficiency | Adrenal hemorrhage/insufficiency Metrorrhagia |
| Hematologic | Jaundice from hemolysis | N/A |
6. Clinically, DIC is very similar to some other clotting and bleeding phenomena. Disorders that must be ruled out include hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, idiopathic purpura fulminans, primary fibrinolysis, thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP-HUS), and vitamin K deficiency. The primary tool for differential diagnosis is a laboratory test that shows excess production of thrombin (Leung, 2006a; Furlong & Furlong, 2005).
7. Laboratory coagulation tests (Cauchie et al., 2006; Song et al., 2006; Toh & Downey, 2005; Geiter, 2003; Taylor et al., 2001) (Table 11-2).
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• A variety of laboratory diagnostic tests show abnormal results with DIC, but some are more sensitive or specific than others. Because of the lack of specificity of most readily available laboratory tests, several researchers have attempted to develop a scoring system to confirm the diagnosis of DIC.
• Three scoring systems have been devised to predict the diagnosis of DIC. Two of the Japanese systems are more sensitive for overt DIC, the other is helpful for indicating candidates for early intervention. The scoring systems are the Japanese Association for Acute Medicine (JAAM) system, the Japanese Ministry of Health and Welfare (JMHW) system, and the International Society on Thrombosis and Haemostasis (ISTH) system (Cauchie et al., 2006; Gando et al., 2006; Taylor et al., 2001).
• All three systems require that a potential risk factor or etiologic factor be identified before the patient’s laboratory values can be scored.
• The most prevalent of the three systems is the ISTH scoring system (Table 11-3) (Taylor et al., 2001). The major difference between the Japanese systems and the ISTH system is that the latter does not require bleeding or organ failure for a diagnosis of DIC. Rather, it is based entirely on laboratory test results. The ISTH system also does not account for the percentage decrease from baseline, as do the Japanese scoring systems (Cauchie et al., 2006; Gando et al., 2006).
| *All scoring systems require the presence of a risk factor for DIC before the laboratory test results can be evaluated. | ||||
| Laboratory Test | 0 | 1 | 2 | 3 |
|---|---|---|---|---|
| Platelet count/mm3 | > 100,000 | > 50,000 | < 50,000 | |
| D-dimer mcg/mL | < 1 | 1-5 | > 5 | |
| Fibrinogen g/L | > 1 | < 1 | ||
| Prothrombin index% | > 70 | 40-70 | < 40 | |
• The defining test for DIC generally is accepted to be validation of excessive production of thrombin.
• Although evident in thrombin formation, fibrinogen levels are not extremely sensitive, because they may begin at higher than normal levels as a result of inflammatory stimuli, and the rate of reduction is inconsistent (Wada et al., 2003).
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