Which condition may contribute to the development of disseminated intravascular?

Disseminated intravascular coagulation can be defined is a widespread hypercoagulable state that can lead to both microvascular and macrovascular clotting and compromised blood flow, ultimately resulting in multiple organ dysfunction syndrome. Commonly, life-threatening illnesses accompany disseminated intravascular coagulation. Treatment centers on identifying and treating the underlying cause. This activity reviews the evaluation and management of disseminated intravascular coagulation and highlights the importance of an interprofessional approach to caring for affected patients.

Objectives:

• Describe the etiology of disseminated intravascular coagulation.

• Describe the clinical manifestations of disseminated intravascular coagulation.

• Explain management considerations for disseminated intravascular coagulation.

• Explain the importance of utilizing an interprofessional team to manage patients with disseminated intravascular coagulation.

Introduction

Disseminated intravascular coagulation (DIC) can be defined as a widespread hypercoagulable state that can lead to both microvascular and macrovascular clotting and compromised blood flow, ultimately resulting in multiple organ dysfunction syndrome or MODS. As this process begins consuming clotting factors and platelets in a positive feedback loop, hemorrhage can ensue, which may be the presenting symptom of a patient with DIC. Disseminated intravascular coagulation typically occurs as an acute complication in patients with underlying life-threatening illnesses such as severe sepsis, hematologic malignancies, severe trauma, or placental abruption. Determining the consequences of DIC and the overall mortality rate of DIC remains difficult as patients with this condition also have additional diagnoses that can cause many of the signs and symptoms consistent with DIC, particularly if they are also suffering from acute or chronic liver failure. While concomitant disease states can obscure a patient’s prognosis, mortality rates have been shown to double in septic patients or those with severe trauma if they are also suffering from DIC.[1][2][3][4][5]

Etiology

Multiple medical conditions can lead to the development of disseminated intravascular coagulation either through a systemic inflammatory response or the release of procoagulants into the bloodstream. The pathological process of DIC has been estimated to occur in up to 30% to 50% of cases of severe sepsis, which is the most common cause of DIC. Classically, DIC has been associated with gram-negative bacteria sepsis, though the prevalence of this disorder in sepsis due to gram-positive organisms may, in fact, be similar. Other causes of sepsis, including parasites, can also lead to DIC. Up to 20% of patients with metastasized adenocarcinoma or lymphoproliferative disease also suffer from DIC in addition to one to five percent of patients with chronic diseases like solid tumors and aortic aneurysms. Obstetrical complications such as placental abruption, hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome), and amniotic fluid embolism have also been known to lead to DIC. Other causes of DIC include trauma, pancreatitis, malignancy, snake bites, liver disease, transplant rejection, and transfusion reactions. About 15.5% of cases of DIC have also been linked to complications occurring after surgery.[6][7][8][9][10][11]

Epidemiology

Because DIC is a complication of other medical diagnoses, the prevalence of DIC remains greater in higher acuity settings as opposed to lower acuity settings. Almost invariably, a severe or life-threatening diagnosis is associated with the disease. A 1996 study in Japan found that a diagnosis of DIC complicated about 1.0% percent of admissions to university hospitals. Similarly, a 1992 study showed DIC complicated 12% of cases of acute lymphoblastic leukemia before starting chemotherapy, and DIC was detected in 78% of cases during remission induction. Furthermore, HELLP syndrome was associated with DIC in approximately one in five cases, according to a 1993 study. [12][13][14][15]

Pathophysiology

Also referred to as consumptive coagulopathy, DIC involves the homeostatic imbalance between coagulation and bleeding. Tissue factor (TF), which may be released into the circulation from vascular endothelial damage from trauma or certain cancer treatments, bacterial endotoxins, or cytokine exposure, activates coagulation factor VII to VIIa in the coagulation pathway. Via the extrinsic pathway, thrombin and fibrin are formed and result in the formation of clots in the circulation. As this process continues, thrombin and fibrin further impair the coagulation cascade through positive feedback loop stimulation and coagulation inhibitor consumption. Clotting factors, as a result, are consumed due to clotting, which can lead to excessive bleeding. Platelets also may become trapped and consumed in this process. Additionally, pathways including the protein C system and antithrombin III appear to be dysregulated in DIC. Furthermore, an increase in plasma activator inhibitor-1 (PAI-1) can prevent the inhibition of fibrinolysis. [11][5]

History and Physical

Components of a patient’s history that may be consistent with disseminated intravascular coagulation include a recent history of severe infections or trauma as well as hepatic failure, obstetric complications, and malignancy. A remote history of deep vein or arterial thromboses may also be suggestive of DIC. Patients may experience bleeding from multiple sites including gingiva, areas of trauma or surgery, the vagina, the rectum, or through devices such as urinary catheters. Symptoms such as hematuria, oliguria, and anuria may be seen if concomitant renal failure from DIC results. Likewise, end-organ damage to the lungs may lead to dyspnea and hemoptysis if pulmonary hemorrhage or pulmonary embolism is occurring and a patient may have mental status change if either thrombi or hemorrhage to areas of the brain arise. A patient could also experience chest pain if arterial occlusion of a coronary artery develops. Regarding signs of DIC on physical exam, obvious bleeding, or frank hemorrhage in various areas of the body may be noted. Skin lesions including ecchymosis, hematomas, jaundice from liver failure, necrosis, and gangrene may also arise. Excessive coagulation may lead to widespread purpura, petechiae, and cyanosis. A patient in DIC may also experience acute respiratory failure or neurological deficits based on the location of bleeding or clots. [16][17][11]

Evaluation

No single history, physical exam, or laboratory component can lead to a diagnosis of or rule out DIC; therefore, a combination of both subjective, objective, and laboratory findings should be utilized to make a diagnosis of DIC. Laboratory findings suggestive of DIC include both an increased prothrombin time (PT) and an increased partial thromboplastin time (PTT), as well as a decreased fibrinogen level as widespread activation and consumption of the clotting cascade occurs. The overall platelet count and hematocrit level may be reduced as well. Schistocytes or fragmented erythrocytes are also commonly seen on a peripheral blood smear. The presence of fibrin split products additionally has a high sensitivity but low specificity for the presence of DIC. A specific scoring system to assess for the presence of DIC was established in 2007. This score includes platelet count, fibrin markers such as D-dimer, prolonged PT, and fibrinogen level with a score over five indicating a high likelihood for overt DIC. [18][19][20][21]

Treatment / Management

The treatment for DIC centers on addressing the underlying disorder, which ultimately led to this condition. Consequently, therapies such as antibiotics for severe sepsis, possible delivery for placental abruption, and possible exploratory surgical intervention for trauma represent the mainstays of treatment for DIC. Platelet and plasma transfusions should only be considered in patients with active bleeding or a high risk of bleeding or those patients requiring an invasive procedure. A common threshold utilized for platelet transfusions in this patient population is less than 50 x 10^9 platelets per liter for actively hemorrhaging patients and 10-20 x 10^9 platelets per liter for those not actively bleeding but at high risk of future bleeding. Likewise, fresh frozen plasma, typically at a dose of 15 mL/kg to 30 mL/kg, and cryoprecipitate can be transfused to replenish coagulation factors. Prothrombin complex concentrate may also be considered; however, this formulation only contains some coagulation factors and will only somewhat correct a patient’s hemostasis. Heparin may also become necessary if a patient has extensive clotting as this medication may prevent further activation of the clotting cascade. Patients with DIC who are not actively bleeding should receive prophylactic anticoagulation with heparin or low molecular weight heparin (LMWH). Other treatment options with human activated protein C, particularly in severe sepsis, may also be effective. [11][19][20][22][5]

Differential Diagnosis

• Hemolytic uremic syndrome

• Heparin-induced thrombocytopenia

• Immune thrombocytopenia (ITC) in emergency medicine

• Thrombotic Thrombocytopenic Purpura (TTP)

Pearls and Other Issues

Disseminated intravascular coagulation can quickly lead to multi-organ failure and death, particularly if early recognition and treatment fail to occur. A high index of suspicion of this high mortality disease in critically ill patients remains paramount to improve outcomes in patients with DIC.

Enhancing Healthcare Team Outcomes

The diagnosis and management of DIC is complex and challenging. The condition is best managed by an interprofessional team that possibly consists of a hematologist, surgeon, intensivist, infectious disease consultant, pathologist, and an internist. The key is to address the underlying disorder that ultimately led to this condition developing. Consequently, therapies such as antibiotics for severe sepsis, possible delivery for placental abruption, and possible exploratory surgical intervention for trauma represent the mainstays of treatment for DIC. Platelet and plasma transfusions should only be considered in patients with active bleeding or a high risk of bleeding or those patients requiring an invasive procedure. Despite optimal treatment, DIC carries a very high mortality rate. Because DIC affects many organ systems, most survivors have a prolonged recovery period. [16][23](Level V)

References

Passmore MR, Obonyo NG, Byrne L, Boon AC, Diab SD, Dunster KR, Fung YL, Spanevello MM, Fauzi MH, Pedersen SE, Simonova G, Anstey CM, Shekar K, Tung JP, Maitland K, Fraser JF. Fluid resuscitation with 0.9% saline alters haemostasis in an ovine model of endotoxemic shock. Thromb Res. 2019 Apr;176:39-45. [PMC free article: PMC7613520] [PubMed: 30776686]

Gonzalez MG, Wei RM, Hatch KD, Gries LM, Hill MG. A Novel Treatment for Massive Hemorrhage after Maternal Trauma in Pregnancy. AJP Rep. 2019 Jan;9(1):e27-e29. [PMC free article: PMC6374146] [PubMed: 30775107]

Nolan S, Czuzoj-Shulman N, Abenhaim HA. Obstetrical and newborn outcomes among women with acute leukemias in pregnancy: a population-based study. J Matern Fetal Neonatal Med. 2020 Oct;33(20):3514-3520. [PubMed: 30773954]

Karakike E, Giamarellos-Bourboulis EJ. Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis. Front Immunol. 2019;10:55. [PMC free article: PMC6365431] [PubMed: 30766533]

Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999 Aug 19;341(8):586-92. [PubMed: 10451465]

Šibíková M, Živný J, Janota J. Cell Membrane-Derived Microvesicles in Systemic Inflammatory Response. Folia Biol (Praha). 2018;64(4):113-124. [PubMed: 30724157]

Komo T, Kohashi T, Aoki Y, Hihara J, Oishi K, Tokumoto N, Kanou M, Nakashima A, Shimomura M, Miguchi M, Mukaida H, Hirabayashi N. Successful surgical management of non-perforating acute appendicitis with septic disseminated intravascular coagulation: A case report and review of the literature. Int J Surg Case Rep. 2019;55:103-106. [PMC free article: PMC6360458] [PubMed: 30716702]

Thachil J. The Elusive Diagnosis of Disseminated Intravascular Coagulation: Does a Diagnosis of DIC Exist Anymore? Semin Thromb Hemost. 2019 Feb;45(1):100-107. [PubMed: 30634199]

Hashimoto D, Okawa T, Maruyama R, Matsumura F, Shibata Y, Kohrogi H. Anticoagulant Therapy for Disseminated Intravascular Coagulation After Gastrointestinal Surgery. Anticancer Res. 2019 Jan;39(1):25-31. [PubMed: 30591437]

Bone RC. Gram-positive organisms and sepsis. Arch Intern Med. 1994 Jan 10;154(1):26-34. [PubMed: 8267486]

Slofstra SH, Spek CA, ten Cate H. Disseminated intravascular coagulation. Hematol J. 2003;4(5):295-302. [PubMed: 14502252]

Matsuda T. Clinical aspects of DIC--disseminated intravascular coagulation. Pol J Pharmacol. 1996 Jan-Feb;48(1):73-5. [PubMed: 9112631]

Okajima K, Sakamoto Y, Uchiba M. Heterogeneity in the incidence and clinical manifestations of disseminated intravascular coagulation: a study of 204 cases. Am J Hematol. 2000 Nov;65(3):215-22. [PubMed: 11074538]

Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol. 1993 Oct;169(4):1000-6. [PubMed: 8238109]

Levi M. Disseminated intravascular coagulation. Crit Care Med. 2007 Sep;35(9):2191-5. [PubMed: 17855836]

Endo S, Shimazaki R., Antithrombin Gamma Study Group. An open-label, randomized, phase 3 study of the efficacy and safety of antithrombin gamma in patients with sepsis-induced disseminated intravascular coagulation syndrome. J Intensive Care. 2018;6:75. [PMC free article: PMC6240214] [PubMed: 30473794]

Chen W, Qi J, Shang Y, Ren L, Guo Y. Amniotic fluid embolism and spontaneous hepatic rupture during uncomplicated pregnancy: a case report and literature review. J Matern Fetal Neonatal Med. 2020 May;33(10):1759-1766. [PubMed: 30394159]

Gando S, Nanzaki S, Kemmotsu O. Disseminated intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after trauma: application of clinical decision analysis. Ann Surg. 1999 Jan;229(1):121-7. [PMC free article: PMC1191617] [PubMed: 9923809]

Venugopal A. Disseminated intravascular coagulation. Indian J Anaesth. 2014 Sep;58(5):603-8. [PMC free article: PMC4260307] [PubMed: 25535423]

Wada H, Thachil J, Di Nisio M, Mathew P, Kurosawa S, Gando S, Kim HK, Nielsen JD, Dempfle CE, Levi M, Toh CH., The Scientific Standardization Committee on DIC of the International Society on Thrombosis Haemostasis. Guidance for diagnosis and treatment of DIC from harmonization of the recommendations from three guidelines. J Thromb Haemost. 2013 Feb 04; [PubMed: 23379279]

Toh CH, Hoots WK., SSC on Disseminated Intravascular Coagulation of the ISTH. The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview. J Thromb Haemost. 2007 Mar;5(3):604-6. [PubMed: 17096704]

Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009 Apr;145(1):24-33. [PubMed: 19222477]

Yoshimura J, Yamakawa K, Kodate A, Kodate M, Fujimi S. Prognostic accuracy of different disseminated intravascular coagulation criteria in critically ill adult patients: a protocol for a systematic review and meta-analysis. BMJ Open. 2018 Dec 04;8(12):e024878. [PMC free article: PMC6286491] [PubMed: 30518591]

Which condition may contribute to the development of disseminated intravascular coagulation?

What are the three most common conditions associated with DIC?

Which event that occurs during disseminated intravascular coagulation DIC may predispose a patient to hemorrhage?

What is the common cause of DIC in obstetrics?