Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC), also known as consumptive coagulopathy, is a pathological activation of coagulation (blood clotting) mechanisms that happens in response to a variety of diseases. As its name suggests, it leads to the formation of small blood clots inside the blood vessels throughout the body.[1] As the small clots consume all the available coagulation proteins and platelets, normal coagulation is disrupted and abnormal bleeding occurs from the skin (e.g. from sites where blood samples were taken), the digestive tract, the respiratory tract and surgical wounds. The small clots also disrupt normal blood flow to organs (such as the kidneys), which may malfunction as a result.[2]
DIC can occur acutely but also on a slower, chronic basis, depending on the underlying problem.[3] It is common in the critically ill, and may participate in the development of multiple organ failure, which may lead to death.[4]
Epidemiology
About half of DIC cases result from complications of pregnancy, and about a third result from carcinomatosis. All other causes make up the remaining sixth of cases.[3]
Pathophysiology
Under homeostatic conditions, the body is maintained in a finely tuned balance of coagulation and fibrinolysis. The activation of the coagulation cascade yields thrombin that converts fibrinogen to fibrin; the stable fibrin clot being the final product of hemostasis. The fibrinolytic system then functions to break down fibrinogen and fibrin. Activation of the fibrinolytic system generates plasmin (in the presence of thrombin), which is responsible for the lysis of fibrin clots. The breakdown of fibrinogen and fibrin results in polypeptides called fibrin degradation products (FDPs) or fibrin split products (FSPs). In a state of homeostasis, the presence of thrombin is critical, as it is the central proteolytic enzyme of coagulation and is also necessary for the breakdown of clots, or fibrinolysis.
In DIC, the processes of coagulation and fibrinolysis lose control, and the result is widespread clotting with resultant bleeding. Regardless of the triggering event of DIC, once initiated, the pathophysiology of DIC is similar in all conditions. One critical mediator of DIC is the release of a transmembrane glycoprotein called tissue factor (TF). TF is present on the surface of many cell types (including endothelial cells, macrophages, and monocytes) and is not normally in contact with the general circulation, but is exposed to the circulation after vascular damage. For example, TF is released in response to exposure to cytokines (particularly interleukin 1), tumor necrosis factor, and endotoxin[5]. This plays a major role in the development of DIC in septic conditions. TF is also abundant in tissues of the lungs, brain, and placenta. This helps to explain why DIC readily develops in patients with extensive trauma. Upon activation, TF binds with coagulation factors that then trigger both the intrinsic and the extrinsic pathways of coagulation.
The release of endotoxin is the mechanism by which Gram-negative sepsis provokes DIC. In acute promyelocytic leukemia, treatment causes the destruction of leukemic granulocyte precursors, resulting in the release of large amounts of proteolytic enzymes from their storage granules, causing microvascular damage. Other malignancies may enhance the expression of various oncogenes that result in the release of TF and plasminogen activator inhibitor-1 (PAI-1), which prevents fibrinolysis.[6]
Excess circulating thrombin results from the excess activation of the coagulation cascade. The excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots in the circulation. These excess clots trap platelets to become larger clots, which leads to microvascular and macrovascular thrombosis. This lodging of clots in the microcirculation, in the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion, and end-organ damage that occurs with DIC.
Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels will permit more clotting so that a feedback system develops in which increased clotting leads to more clotting. At the same time, thrombocytopenia occurs because of the entrapment and consumption of platelets. Clotting factors are consumed in the development of multiple clots, which contributes to the bleeding seen with DIC.
Simultaneously, excess circulating thrombin assists in the conversion of plasminogen to plasmin, resulting in fibrinolysis. The breakdown of clots results in excess amounts of FDPs, which have powerful anticoagulant properties, contributing to hemorrhage. The excess plasmin also activates the complement and kinin systems. Activation of these systems leads to many of the clinical symptoms that patients experiencing DIC exhibit, such as shock, hypotension, and increased vascular permeability. The acute form of DIC is considered an extreme expression of the intravascular coagulation process with a complete breakdown of the normal homeostatic boundaries. DIC is associated with a poor prognosis and a high mortality rate.
Causes
DIC can occur in the following conditions:[7][4][3]
- Cancers of lung, pancreas, prostate and stomach
- Obstetric: abruptio placentae, retained dead fetus, pre-eclampsia, amniotic fluid embolism
- Massive tissue injury: Trauma, burns, extensive surgery
- Infections: Gram-negative sepsis, Neisseria meningitidis, Streptococcus pneumoniae, malaria, histoplasmosis, aspergillosis, Rocky mountain spotted fever
- Miscellaneous: Liver disease, snake bite, acute intravascular hemolysis, giant hemangioma, shock, heat stroke, vasculitis, aortic aneurysm, Serotonin syndrome[8]
Signs and symptoms
The affected person is often acutely ill and shocked with widespread haemorrhage (common bleeding sites are mouth, nose and venipuncture sites), extensive bruising, renal failure and gangrene.[7][9] The onset of DIC can be fulminant, as in endotoxic shock or amnioitic fluid embolism, or it may be insidious and chronic, as in cases of carcinomatosis or retention of dead fetus.[3]
Diagnosis
Diagnosis is usually suggested by following conditions:[7]
- Severe cases with haemorrhage: The PT and APTT are usually very prolonged and the fibrinogen level markedly reduced. High levels of fibrin degradation products, including D-dimer, are found owing to the intense fibrinolytic activity stimulated by the presence of fibrin in the circulation. There is severe thrombocytopenia. The blood film may show fragmented red blood cells (schistocytes).
- Mild cases without bleeding: There is increased synthesis of coagulation factors and platelets. PT, APTT, and platelet counts are normal. fibrin degradation products are raised.
Definitive diagnosis depends on the result of: [10]
- Thrombocytopenia
- Prolongation of prothrombin time and activated partial thromboplastin time
- A low fibrinogen concentration
- Increased levels of fibrin degradation products
Treatment
The only effective treatment is the reversal of the underlying cause. Anticoagulants are given exceedingly rarely when thrombus formation is likely to lead to imminent death (such as in coronary artery thrombosis or cerebrovascular thrombosis). Platelets may be transfused if counts are less than 5,000-10,000/mm3 and massive hemorrhage is occurring, and fresh frozen plasma may be administered in an attempt to replenish coagulation factors and anti-thrombotic factors, although these are only temporizing measures and may result in the increased development of thrombosis.
DIC results in lower fibrinogen levels (as it has all been converted to fibrin), and this can be tested for in the hospital lab. A more specific test is for "fibrin split products" (FSPs) or "fibrin degradation products" (FDPs) which are produced when fibrin undergoes degradation when blood clots are dissolved by fibrinolysis.
In some situations, infusion with antithrombin may be necessary. A new development is drotrecogin alfa (Xigris), a recombinant activated protein C product. Activated Protein C (APC) deactivates clotting factors V and VIII, and the presumed mechanism of action of drotrecogin is the cessation of the intravascular coagulation. Due to its high cost and its severe adverse effects, it is only used strictly on indication in intensive care patients with severe sepsis.[11] The large, multicenter ENHANCE trial provided more evidence that there may be a favorable benefit/risk ratio to administering activated protein C in adults[12], but was unable to make definitive conclusions about efficacy due to the lack of a placebo control, and particularly in children, there is a high risk of hemorrhage (27.4% in patients aged 0-18 years)[13]
Prognosis
Prognosis varies depending on the underlying disorder. The prognosis for those with DIC, regardless of cause, is often grim, leading the initials to be known colloquially as "death is coming".[14]
See also
References
- ↑ Churchill Livingstone Pocket Medical Dictionary 14th Edition.
- ↑ ISBN 0-443-07036-9 Davidson's Principles and Practice of Medicine 19th Edition. Churchill Livingstone. Page 200
- ↑ 3.0 3.1 3.2 3.3 Robbins, Stanley L.; Cotran, Ramzi S.; Kumar, Vinay; Collins, Tucker (1999). Robbins' Pathologic Basis of Disease (6 ed.). Philadelphia: Saunders. ISBN 0-7216-7335-X.
- ↑ 4.0 4.1 Davidson, Stanley; Haslett, C. (2002). Davidson's Principles and Practice of Medicine (19 ed.). Edinburgh: Churchill Livingstone. ISBN 0-443-07036-9.
- ↑ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; & Mitchell, Richard N. (2007). Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. 469-471 ISBN 978-1-4160-2973-1
- ↑ Rak J, Yu JL, Luyendyk J, Mackman N (2006). "Oncogenes, trousseau syndrome, and cancer-related changes in the coagulome of mice and humans". Cancer Res. 66 (22): 10643–6. doi:10.1158/0008-5472.CAN-06-2350. PMID 17108099. http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17108099.
- ↑ 7.0 7.1 7.2 Clark, Michael; Kumar, Parveen J. (1998). Clinical Medicine: A Textbook for Medical Students and Doctors (4 ed.). Philadelphia: W.B. Saunders. ISBN 0-7020-2458-9.
- ↑ Boyer EW, Shannon M (2005). "The serotonin syndrome". N. Engl. J. Med. 352 (11): 1112–20. doi:10.1056/NEJMra041867. PMID 15784664.
- ↑ Oxford Handbook of Clinical Medicine 6th Edition. Page 650
- ↑ ISBN 0-443-07036-9 Davidson's Principles and Practice of Medicine 19th Edition. Churchill Livingstone. Page 953.
- ↑ Dhainaut J, Yan S, Joyce D, Pettilä V, Basson B, Brandt J, Sundin D, Levi M (2004). "Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation.". J Thromb Haemost 2 (11): 1924–33. doi:10.1111/j.1538-7836.2004.00955.x. PMID 15550023.
- ↑ Vincent JL, Bernard GR, Beale R, et al (2005). "Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment". Crit. Care Med. 33 (10): 2266–77. doi:10.1097/01.CCM.0000181729.46010.83. PMID 16215381. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0090-3493&volume=33&issue=10&spage=2266.
- ↑ Goldstein B, Nadel S, Peters M, et al (2006). "ENHANCE: results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis". Pediatr Crit Care Med 7 (3): 200–11. doi:10.1097/01.PCC.0000217470.68764.36. PMID 16575354. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?doi=10.1097/01.PCC.0000217470.68764.36.
- ↑ Norman K (2004). "Alternative treatments for disseminated intravascular coagulation.". Drug News Perspect 17 (4): 243–50. doi:10.1358/dnp.2004.17.4.829051. PMID 15334173.
Diseases of the skin and appendages by morphology |
|
Growths |
Epidermal
|
verruca, clavus, seborrheic keratosis, acrochordon, molluscum contagiosum, actinic keratosis, squamous cell carcinoma, basal cell carcinoma, merkel cell carcinoma, nevus sebaceous, trichoepithelioma
|
|
Pigmented
|
|
|
Dermal and subcutaneous
|
epidermal inclusion cyst, hemangioma, dermatofibroma, keloid, lipoma, neurofibroma, xanthoma, Kaposi's sarcoma, infantile digital fibromatosis, granular cell tumor, leiomyoma, lymphangioma circumscriptum, myxoid cyst
|
|
|
Rashes |
With epidermal involvement
|
Eczematous
|
essential dermatitis, contact dermatitis, atopic dermatitis, seborrheic dermatitis, stasis dermatitis, lichen simplex chronicus, Darier's disease, glucagonoma syndrome, langerhans cell histiocytosis, lichen sclerosus, pemphigus foliaceus, Wiskott-Aldrich syndrome, Zinc deficiency
|
|
Scaling
|
psoriasis, tinea corporis, tinea cruris, tinea pedis, tinea manuum, tinea faciale, pityriasis rosea, secondary syphillis, mycosis fungoides, systemic lupus erythematosus, pityriasis rubra pilaris, parapsoriasis, icthyosis
|
|
Blistering
|
herpes simplex, herpes zoster, varicella, bullous impetigo, acute contact dermatitis, pemphigus vulgaris, bullous pemphigoid, dermatitis herpetiformis, porphyria cutanea tarda, epidermolysis bullosa simplex
|
|
Papular
|
scabies, insect bite reactions, lichen planus, miliaria, keratosis pilaris, lichen spinulosus, transient acantholytic dermatosis, lichen nitidus, pityriasis lichenoides et varioliformis acuta
|
|
Pustular
|
|
|
Hypopigmented
|
tinea versicolor, vitiligo, pityriasis alba, postinflammatory hypopigmentation, tuberous sclerosis, idiopathic guttate hypomelanosis, leprosy, hypopigmented mycosis fungoides
|
|
|
Without epidermal involvement
|
Red
|
Blanchable Erythema
|
Generalized
|
|
|
Localized
|
cellulitis, abscess, furuncle, erythema nodosum, carcinoid syndrome, carcinoma erysipeloides, fixed drug eruption
|
|
Specialized
|
urticaria, erythema multiforme, erythema migrans, erythema gyratum repens, erythema annulare centrifugum, erythema ab igne
|
|
|
Nonblanchable Purpura
|
Macular
|
thrombocytopenic purpura, actinic purpura
|
|
Papular
|
disseminated intravascular coagulation, vasculitis
|
|
|
|
Indurated
|
scleroderma/morphea, granuloma annulare, lichen sclerosis et atrophicus, necrobiosis lipoidica
|
|
|
|
Miscellaneous |
Ulcers
|
|
|
Hair disorders
|
|
|
Nail disorders
|
|
|
Mucous membrane disorders
|
aphthous stomatitis, oral candidiasis, lichen planus, leukoplakia, pemphigus vulgaris, mucous membrane pemphigoid, cicatricial pemphigoid, herpesvirus, coxsackievirus, syphilis, systemic histoplasmosis, squamous cell carcinoma
|
|
|
Pathology: hematology · myeloid hematologic disease (primarily D50-D77 · 280-289) |
|
RBCs/
hemoglobinopathy |
+
|
Polycythemia · Macrocytosis
|
|
·
|
|
Nutritional
|
Iron deficiency anemia (Plummer-Vinson syndrome) · Megaloblastic anemia ( Pernicious anemia)
|
|
Hemolytic
|
Hereditary
|
enzyme: G6PD Deficiency · Pyruvate kinase deficiency · Triosephosphate isomerase deficiency
hemoglobin: Thalassemia · Sickle-cell disease/trait
membrane: Hereditary spherocytosis · Hereditary elliptocytosis · Hereditary stomatocytosis
|
|
Acquired
|
Autoimmune (Warm, Cold) · MAHA · Myelophthisic
combinations: HUS · hemoglobinuria (PNH, PCH)
|
|
|
Aplastic
|
Acquired PRCA · Diamond-Blackfan anemia · Fanconi anemia · Sideroblastic anemia
|
|
Blood tests
|
MCV (Normocytic, Microcytic, Macrocytic) · MCHC (Normochromic, Hypochromic)
|
|
|
Other
|
Methemoglobinemia
|
|
|
|
Coagulation/platelets/
coagulopathy/
bleeding diathesis |
+
|
Hypercoagulability
|
primary: Antithrombin III deficiency · Protein C deficiency/Activated protein C resistance/Protein S deficiency/Factor V Leiden · Hyperprothrombinemia
acquired: DIC (Congenital afibrinogenemia, Purpura fulminans) · autoimmune ( Antiphospholipid)
|
|
Other
|
Essential thrombocytosis
|
|
|
·
|
clotting factor: Hemophilia (A/VIII, B/IX, C/XI) • Von Willebrand disease • Hypoprothrombinemia/II · XIII
platelet function: Bernard-Soulier syndrome · Glanzmann's thrombasthenia · Hermansky-Pudlak syndrome · Gray platelet syndrome · May Hegglin anomaly · Pelger-Huet anomaly
Purpura: Henoch-Schönlein · TP · ITP (Evans syndrome) · TTP
Thrombocytopenia (Heparin-induced thrombocytopenia)
|
|
|
Monocytes/
macrophages |
+
|
Histiocytosis
|
WHO-I (Langerhans cell histiocytosis)
WHO-II/non-Langerhans-cell (Juvenile xanthogranuloma, Hemophagocytic lymphohistiocytosis)
WHO-III/malignant (Acute monocytic leukemia, Malignant histiocytosis, Erdheim-Chester disease)
|
|
Other
|
|
|
|
·
|
-penia: Monocytopenia
|
|
|
Granulocytes |
+
|
-cytosis: granulocytosis (Neutrophilia, Eosinophilia, Basophilia)
|
|
·
|
|
|
|
See also hematological malignancy and immune disorders
|
|