Disseminated intravascular coagulation is a pathological activation of the coagulation mechanisms (1).the subcommittee on DIC of the international society on Thrombosis and haemostasis had suggested the following definition for DIC: 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, which if sufficiently sever, can produce organ dysfunction (2). It leads to formation of small blood clots inside the blood vessels throughout the body (1). As the small clots use up the clotting factors the normal clotting procedure is disrupted. This results in bleeding from skin, digestive tract and from surgical wounds. The small blood clots disturb blood flow to organs causing malfunction of that organs.
Clotting Mechanism
The clotting system like complement system is a proteolytic cascade. Each enzyme of the pathway is present as zymogens, which on activation undergoes proteolytic cleavage to release the activated factor from the precursor molecule. The ultimate goal of this pathway is to produce thrombin which converts the soluble fibrinogen to insoluble fibrin which forms a clot (3). The generation of thrombin can be divided to intrinsic, extrinsic and common pathways.
Intrinsic pathway.
The intrinsic pathway is activated when blood is activated when blood comes in contact with sub endothelial connective tissue(collagen) or negatively charged surfaces as a result of tissue damage. Quantitatively this is the most important of the two pathways but slower to cleave fibrin than extrinsic

pathway. The function of the pathway is to activate the inactive factor X to active factor X. Factors involved in intrinsic pathway are (3).
Factor XII – Hageman factor
Factor XI
Prekallikrein
High molecular weight kininogen–HMWK
The intrinsic pathway begins with the formation of the primary complex on sub endothelial collagen by HMWK, prekallikrein and Hegman factor. Prekallikrein is converted to kallikrein and inactive factor xII (XII) becomes active factor XII (XIIa).XIIa converts inactive factor XI (XI) to factor XI (XIa).This activation is also done with compliment of the factor VII of the extrinsic pathway. The activated IX with its cofactor VII form the Tenase complex which converts the X to Xa. (4)
INTRINSIC PATHWAY
HMW kininogen, Kallikrein

XII XIIa

VIIa

XI XIa
VIII VIIIa, PL, Ca+2
X Xa
Extrinsic pathway
Extrinsic pathway is an alternative pathway for activation of the clotting cascade. It provides a very rapid response to tissue injury, generating activated factor X almost instantaneously, compared to the seconds to even minutes required to the intrinsic pathway to activate the factor X. The main function of the extrinsic pathway is to augment the action of the intrinsic pathway (3). The factors unique to the extrinsic pathway are,
Factor III-Tissue factor
Factor VII
Following damage to a blood vessel endothelium tissue factorIII is released, forming a complex with factor VII and so doing it activating it to VIIa. This complex activates IX and X. The activation by VIIa is inhibited by the Tissue Factor pathway Inhibitor (TFI). (5)

EXTRINSIC PATHWAY
TPL TFI

VII VIIa IX XIa
V Va
PL,Ca+2
X Xa

Common pathway
The intrinsic pathway and extrinsic pathways converge at factor X to single common pathway. The activated factors X with its co-factor Va forms the prothrombinase complex which activates the prothrombin to thrombin. Thrombin then activates the other components of the clotting cascade. They include activation of fibrinogen to fibrin, the building block of haemostatic plug. In addition, it activates factors VII and V and their inhibitor protein C (in the presence of Thrombomodulin), and it activates factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers (5).
IX IXa
VIIa PL
Va,Ca2+
X Xa

Prothrombin (II) Thrombin (IIa)

Fibrinogen Fibrin Monomer

Cross linked fibrin network

Disseminated Intravascular Coagulation
DIC is a condition in which small blood clots develops through the bloodstream, blocking small blood vessels and depleting. The increased clotting depletes the platelets and and clotting factors needed to control the bleeding, causes extensive bleeding.
DIC begins with extensive clotting. This is usually stimulated by a substance that enters the blood as a part of a disease (such as an infection or certain cancer) or as a complication of a childbirth, retention of a dead fetus, or surgery. People with head injury or who have been bitten by a poisonous snake is also at risk. As clotting factors and platelets depleted, extensive bleeding occurs (6).

Causes
Causes of DIC can be classified as acute or chronic, systemic or localized. DIC may be the result of a single or multiple conditions.
• Acute DIC
o Infectious
 Bacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial)
 Viral (eg, HIV, cytomegalovirus [CMV], varicella, hepatitis)
 Fungal (eg, Histoplasma)
 Parasitic (eg, malaria)
o Malignancy
 Hematologic (eg, acute myelocytic leukemias)
 Metastatic (eg, mucin-secreting adenocarcinomas)

o Obstetric
 Placental abruption
 Amniotic fluid embolism
 Acute fatty liver of pregnancy
 Eclampsia
o Trauma
o Burns
o Motor vehicle accidents (MVAs)
o Snake envenomation
o Transfusion
o Hemolytic reactions
o Massive transfusion
o Liver disease – Acute hepatic failure
o Prosthetic devices
o Shunts (Denver, LeVeen)
o Ventricular assist devices(8)

Infection
Infection is the common cause of disseminated intravascular coagulation. About 10%-20% of patients with Gram negative bacteraemia have evidence of disseminated intravascular coagulation, but Gram positive organisms may also be responsible, particularly patients with hyposplenism. Systemic viral infections, malaria, viral hemorrhagic fever, herpes, and influenza viruses are also recognized as causes.(8)

Obstetric complications
Placental separation and amniotic fluid embolism probably results in release of placental tissue factor and
a direct activator of the prothrombinase complex into the maternal circulation. Rapid resolution of disseminated intravascular coagulation after evacuation of the uterus suggests that the placenta is responsible for the persistent stimulus to disseminated intravascular coagulation.(8)
Trauma
A combination of mechanisms, including the release of fat and phospholipids from tissue into the circulation, hemolysis, and endothelial damage, may promote the systemic activation of coagulation. In addition, there is emerging evidence that cytokines have a pivotal role in the development of disseminated intravascular coagulation, since the systemic activation patterns of cytokines are virtually identical in patients with polytrauma and patients with sepsis(10).

Transfusion of incompatible ABO red cells
Transfusion of incompatible red cells can cause rapid disseminated intravascular coagulation. Naturally occurring IgM antibodies combine with A or B antigens on the surfaces of the transfused red cells to form complement activating immune complexes. Disseminated intravascular coagulatin is the result of the endothelial damage caused by assembly of the complement membrane attack complex rather than destruction of the red blood cells. Non-immune intravascular haemolysis is not associated with disseminated intravascular coagulation.

Liver disease
Liver disease associated with acute disseminated intravascular coagulation when there is acutehapatic necrosis, fatty liver of pregnancy, or insertion if a LeVeen shunt in a patient with chronic liver disease and acites.
Giant Hemangiomas
Giant hemangiomas (the Kasabach–Merritt syndrome) and even large aortic aneurysms may result in local activation of coagulation. In patients with these conditions, local activation of coagulation most commonly results in the systemic depletion of locally consumed coagulation factors and platelets, but activated coagulation factors can reach the systemic circulation and cause disseminated intravascular coagulation. The incidence of clinically overt disseminated intravascular coagulation is 25 percent among patients with giant hemangiomas, whereas the incidence is approximately 0.5 to 1 percent among patients with large aortic aneurysms (10).

• Chronic DIC
o Malignancies
 Solid tumors
 Leukemia
o Obstetric
 Retained dead fetus syndrome
 Retained products of conception
o Hematologic
 Myeloproliferative syndromes
 Paroxysmal nocturnal hemoglobinuria
o Vascular
 Rheumatoid arthritis
 Raynaud disease
o Cardiovascular – Myocardial infarction
o Inflammatory
 Ulcerative colitis
 Crohn disease
 Sarcoidosis
• Localized DIC
o Aortic aneurysms
o Giant hemangiomas (Kasabach-Merritt syndrome)
o Acute renal allograft rejection
o Hemolytic uremic syndrome(8)
Malignancy
Adenocarcinoma is a common cause. Recurrent venous thrombolism is a particular feature of this form of disseminated intravascular coagulation (Trousseau’s syndrome), and recurrence may be prevented by heparin but typically not wafferin. Carcinoma may cause disseminated intravascular coagulation by invasion of tissue and releasing tissue factor, or direct activation of the prothrombinase complex by mucin or a specific cancer procoagulent.(8)
Retained dead fetus
Retained dead fetus syndrome causes progressive disseminated intravascular coagulation over several weeks. At first mother can compensate for this, and the initial fall in fibrinogen concentration often falls that about 1 g/L.A t this stage production and consumption of fibrinogen seem to be in a equilibrium, andthis steady rate may persist for few days. However severe hypocoagulopathyeventuallyoccurs unless the uterus is removed.(8)
Liver disease
Liver disease may be a cause of disseminated intravascular coagulation, but it’s not very clear whether the intravascular coagulation is a major component of the coagulopathy of the major liver disease. The prolonged survival of the radiolabled fibrinogen in the circulation after the administration of heparin is the strongest evidence for coagulopathy in patients with liver failure, but it doesn’t seem to be a major contribution to the coagulopathy.(7)
Pathophysiology
DIC is caused by widespread and ongoing activation of coagulation, leading to vascular or microvascular fibrin deposition, thereby compromising an adequate blood supply to various organs. Four different mechanisms are primarily responsible for the hematologic derangements seen in DIC: increased thrombin generation, a suppression of anticoagulant pathways, impaired fibrinolysis, and inflammatory activation. Activation of intravascular coagulation is mediated almost entirely by the intrinsic clotting pathway.

Exposure to tissue factor in the circulation occurs via endothelial disruption, tissue damage, or inflammatory or tumor cell expression of procoagulant molecules, including tissue factor. Tissue factor

activates coagulation by the intrinsic pathway involving factor VIIa. Factor VIIa has been implicated as the central mediator of intravascular coagulation in sepsis. Blocking the factor VIIa pathway in sepsis has been shown to prevent the development of DIC, whereas interrupting alternative pathways did not demonstrate any effect on clotting. The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation. Evidence suggests that the intrinsic (or contact) pathway is also activated in DIC, while contributing more to hemodynamic instability and hypotension than to activation of clotting.

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Antithrombin is one such mechanism responsible for regulating thrombin levels. However, due to multiple factors, antithrombin activity is reduced in patients with sepsis. First, antithrombin is continuously consumed by ongoing activation of coagulation. Moreover, elastase produced by activated neutrophils degrades antithrombin as well as other proteins. Further antithrombin is lost to capillary leakage. Lastly, production of antithrombin is impaired secondary to liver damage resulting from under-perfusion and microvascular coagulation. Decreased levels of antithrombin correlate well with elevated mortality in patients with sepsis. (8)
Protein C, along with protein S, serves as an important anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin and is complexed on the endothelial cell surface with thrombomodulin. Activated protein C combats coagulation via proteolytic cleavage of factors Va and VIIIa. However, the cytokines (tumor necrosis factor α [TNF-a], interleukin 1 [IL-1]) produced in sepsis and other generalized inflammatory states largely incapacitate the protein C pathway. Inflammatory cytokines down-regulate the expression of thrombomodulin on the endothelial cell surface. Protein C levels are further reduced via consumption, extravascular leakage, and reduced hepatic production and by a reduction in freely circulating protein S.(8) In addition to the decrease in antithrombin III, a significant
activates coagulation by the intrinsic pathway involving factor VIIa. Factor VIIa has been implicated as the central mediator of intravascular coagulation in sepsis. Blocking the factor VIIa pathway in sepsis has been shown to prevent the development of DIC, whereas interrupting alternative pathways did not demonstrate any effect on clotting. The tissue factor-VIIa complex then serves to activate thrombin, which, in turn, cleaves fibrinogen to fibrin while simultaneously causing platelet aggregation. Evidence suggests that the intrinsic (or contact) pathway is also activated in DIC, while contributing more to hemodynamic instability and hypotension than to activation of clotting(8).

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Antithrombin is one such mechanism responsible for regulating thrombin levels. However, due to multiple factors, antithrombin activity is reduced in patients with sepsis(10). First, antithrombin is continuously consumed by ongoing activation of coagulation. Moreover, elastase produced by activated neutrophils degrades antithrombin as well as other proteins. Further antithrombin is lost to capillary leakage. Lastly, production of antithrombin is impaired secondary to liver damage resulting from under-perfusion and microvascular coagulation. Decreased levels of antithrombin correlate well with elevated mortality in patients with sepsis. (8)
Protein C, along with protein S, serves as an important anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin and is complexed on the endothelial cell surface with thrombomodulin. Activated protein C combats coagulation via proteolytic cleavage of factors Va and VIIIa. However, the cytokines (tumor necrosis factor α [TNF-a], interleukin 1 [IL-1]) produced in sepsis and other generalized inflammatory states largely incapacitate the protein C pathway.(10) Inflammatory cytokines down-regulate the expression of thrombomodulin on the endothelial cell surface. Protein C levels are further reduced via consumption, extravascular leakage, and reduced hepatic production and by a reduction in freely circulating protein S.(8) In addition to the decrease in antithrombin III, a significant
depression of the protein C system may occur. This impaired function of the protein C pathway is mainly due to downregulation of thrombomodulin expression on endothelial cells by proinflammatory cytokines, like tumor necrosis factor-alpha (TNF-alpha) and interleukin 1b (IL-1b). The downregulation of thrombomodulin has been confirmed in studies in patients with meningococcal sepsis. This, in combination with low levels of zymogen protein C (due to similar mechanisms as described for antithrombin), results in diminished protein C activation, which will enhance the procoagulant state.
Animal experiments of severe inflammation-induced coagulation activation convincingly show that compromising the protein C system results in increased morbidity and mortality, whereas restoring an adequate function of activated protein C improves survival and organ failure.(2)
Tissue factor pathway inhibitor (TFPI) is another anticoagulant mechanism that is disabled in DIC. TFPI inhibits the tissue factor-VIIa complex. Although levels of TFPI are normal in patients with sepsis, a relative insufficiency in DIC is evident. TFPI depletion in animal models predisposes to DIC, and TFPI blocks the procoagulant effect of endotoxin in humans. The intravascular fibrin produced by thrombin is normally eliminated via a process termed fibrinolysis(8). The initial response to inflammation appears to be augmentation of fibrinolytic action; however, this response soon reverses as inhibitors (plasminogen activator inhibitor-1 [PAI-1], TAFI) of fibrinolysis are released. Indeed, high levels of PAI-1 precede DIC and predict poor outcomes(9). Fibrinolysis cannot keep pace with increased fibrin formation, eventually resulting in under-opposed fibrin deposition in the vasculature.

Inflammatory and coagulation pathways interact in substantial ways. Many of the activated coagulation factors produced in DIC contribute to the propagation of inflammation by stimulating endothelial cell release of proinflammatory cytokines. Factor Xa, thrombin, and the tissue factor-VIIa complex have each been demonstrated to elicit proinflammatory action. Furthermore, given the anti-inflammatory action of activated protein C and AT, their impairment in DIC contributes to further dysregulation of inflammation.
Components of DIC include the following
• Exposure of blood to procoagulant substances
• Fibrin deposition in the microvasculature
• Impaired fibrinolysis
• Depletion of coagulation factors and platelets (consumptive coagulopathy)
• Organ damage and failure(8)
Mortility and morbidity
Morbidity and mortality depend on both the underlying disease and the severity of coagulopathy. Assigning a numerical figure for DIC-specific morbidity and mortality is difficult. Below are examples of mortality rates in diseases complicated by DIC:
• Idiopathic purpura fulminans associated with DIC has a mortality rate of 18%.
• Septic abortion with clostridial infection and shock associated with severe DIC has a mortality rate of 50%.
• In the setting of major trauma, the presence of DIC approximately doubles the mortality rate(2)

Obviously, the clinical importance of a severe depletion of platelets and coagulation factors in patients with diffuse, widespread bleeding or in patients who need to undergo an invasive procedure is clear. In addition, the intravascular deposition of fibrin, as a result of the systemic activation of coagulation, contributes to organ failure and mortality.
Histological studies in patients with disseminated intravascular coagulation (DIC) show the presence of ischemia and necrosis due to fibrin deposition in small- and mid-size vessels of various organs. The presence of these intravascular thrombi appears to be clearly and specifically related to the clinical dysfunction of the organ. Specific thrombotic complications that are sometimes seen in the framework of disseminated intravascular coagulation (DIC) are acral cyanosis, hemorrhagic skin infarctions, and limb ischemia.
Secondly, experimental animal studies of disseminated intravascular coagulation (DIC) show fibrin deposition in various organs. Amelioration of disseminated intravascular coagulation (DIC) by various interventions appears to improve organ failure and, in some but not all cases, mortality.
Lastly, disseminated intravascular coagulation (DIC) has been shown to be an independent predictor of mortality in patients with sepsis and severe trauma. The presence of disseminated intravascular coagulation (DIC) may increase the risk of death by 1.5 to 2.0 in various studies. An increasing severity of disseminated intravascular coagulation (DIC) is directly related to an increased mortality.(8)
Diagnosis
There is no single laboratory test that can establish or rule out the diagnosis of disseminated intravascular coagulation. However, a combination of test results in a patient with a clinical condition known to be associated with disseminated intravascular coagulation can be used to diagnose the disorder with reasonable certainty in most cases. In clinical practice the disorder can be diagnosed on the basis of the following findings: an underlying disease known to be associated with disseminated intravascular coagulation; an initial platelet count of less than 100,000 per cubic millimeter or a rapid decline in the platelet count; prolongation of clotting times, such as the prothrombin time and the activated partial-thromboplastin time; the presence of fibrin-degradation products in plasma; and low plasma levels of coagulation inhibitors, such as antithrombin III(10).
Laboratory Studies
• No single routinely available laboratory test is sufficiently sensitive or specific to allow a diagnosis of disseminated intravascular coagulation (DIC).
• Specialized tests
o In a specialized setting, molecular markers for activation of coagulation or fibrin formation may be the most sensitive assays for disseminated intravascular coagulation (DIC). A number of clinical studies show that the presence of soluble fibrin in plasma has a 90-100% sensitivity for the diagnosis of disseminated intravascular coagulation (DIC), but unfortunately the specificity is low. Another problem is that a reliable test for quantifying soluble fibrin in plasma is not available, and one study showed a wide discordance among various assays.
o The dynamics of disseminated intravascular coagulation (DIC) can also be judged by measuring activation markers that are released upon the conversion of a coagulation factor zymogen to an active protease, such as prothrombin activation fragment F1+2 (F1+2). Indeed, these markers are markedly elevated in patients with disseminated intravascular coagulation (DIC), but, again, the specificity is a problem.
o In addition to these shortcomings, most of the sensitive and sophisticated tests described above are not available to general hematology laboratories. Although these tests may be very helpful in clinical trials or other research, they often cannot be used in a routine setting.
• Routine tests
o In clinical practice, a diagnosis of disseminated intravascular coagulation (DIC) can often be made by a combination of platelet count, measurement of global clotting times (aPTT and PT), measurement of 1 or 2 clotting factors and inhibitors (eg, antithrombin), and a test for fibrin degradation products (FDPs). It should be emphasized that serial coagulation tests are usually more helpful than single laboratory results in establishing the diagnosis of disseminated intravascular coagulation (DIC). A reduction in the platelet count or a clear downward trend at subsequent measurements is a sensitive (although not specific) sign of disseminated intravascular coagulation (DIC).
o The prolongation of global clotting times may reflect the consumption and depletion of various coagulation factors, which may be further substantiated by the measurement of selected coagulation factors, such as Factor V and facor VIII.
o Measurement of coagulation factors may also may be helpful to detect additional hemostatic abnormalities (eg, those caused by Vitamin k deficiency)
Management
The cornerstone of the management of disseminated intravascular coagulation is the treatment of the underlying disorder. Treatment of disseminated intravascular coagulation without treatment of the underlying cause is predestined to fail. Supportive measures may be necessary, although firm evidence on which to base management is scarce, and there is no consensus regarding the optimal treatment or supportive strategy. A patient with disseminated intravascular coagulation who has diffuse bleeding from various sites at presentation will need different supportive treatment from

what is appropriate for a patient with thrombotic obstruction of the vasculature and subsequent multiorgan failure(10).
Anticoagulants
Theoretically, interruption of coagulation should be of benefit in patients with disseminated intravascular coagulation.(11) Indeed, experimental studies have shown that heparin can partially inhibit the activation of coagulation in cases that are related to sepsis or other causes. Adequate prophylaxis is also needed to eliminate the risk of venous thromboembolism. Heparin has been shown to have a beneficial effect in small, uncontrolled studies of patients with disseminated intravascular coagulation, but not in controlled clinical trials(10).
Platelets and Plasma
Low levels of platelets and coagulation factors may cause serious bleeding or may increase the risk of bleeding in patients who require an invasive procedure. In such patients, the efficacy of treatment with platelet concentrate and plasma has clearly been shown. Treatment with coagulation-factor concentrates may overcome the need for large infusions of plasma, but their use in patients with disseminated intravascular coagulation is generally not advocated because the concentrates may be contaminated with traces of activated coagulation factors, which could exacerbate the coagulation disorder(10).
Trearment
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. The large, multicenter ENHANCE trial provided more
evidence that there may be a favorable benefit/risk ratio to administering activated
protein C in adults, 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)(12)
Below passage contians results in a research of treatment of DIC sarried out by Marcel M Levi, MD:-
{Gabexate mesilate (FOY) was used to treat 215 patients with disseminated intravascular coagulation (DIC) and 146 patients with a predisposition to DIC (pre-DIC). Sixty percent of DIC patients and 48% of pre-DIC patients exhibited pretreatment organ failure, which resolved after FOY treatment in 16% of DIC patients and 17% of pre-DIC patients. Seventy percent of DIC patients and 49% of pre-DIC patients had a pretreatment bleeding tendency that was ameliorated by FOY treatment in 32% of DIC patients and 30% of pre-DIC patients. Comparison of pretreatment and posttreatment hemostatic studies of the DIC patients revealed that platelet count and levels of fibrinogen degradation products (FDP), thrombin-antithrombin-III complex, and FDP-D-dimer decreased significantly; fibrinogen level increased markedly; and prothrombin time was prolonged. DIC scores were significantly lowered in both leukemic and nonleukemic patients from the third day of treatment with FOY. Among leukemic DIC patients, 59% showed complete remission (CR), 21% partial remission (PR), and 7% exacerbation of their condition; 46% of the nonleukemic DIC patients demonstrated CR, 17% PR, and 17% exacerbation. Of the leukemic pre-DIC patients, 59% showed improvement and 7% exacerbation, whereas 55% of the nonleukemic pre-DIC patients showed improvement and 27% exacerbation}(9)