Disseminated intravascular coagulation (DIC) is characterized by systemic activation of blood coagulation, which results in generation and deposition of fibrin, leading to microvascular thrombi in various organs and contributing to multiple organ dysfunction syndrome (MODS). Consumption and subsequent exhaustion of coagulation proteins and platelets may induce severe bleeding.

The International Society on Thrombosis and Haemostasis has suggested the following definition for DIC: An acquired syndrome characterized by the intravascular activation of coagulation with a simultaneously occurring thrombotic and bleeding problem, which obviously complicates the proper treatment.

DIC is not itself a specific illness; rather, it is a complication or an effect of the progression of other illnesses. It is always secondary to an underlying disorder and is associated with a number of clinical conditions such as sepsis and severe infection, trauma, organ destruction, malignancy, and so on.

DIC can be divided into acute DIC and chronic DIC. Acute DIC develops when sudden exposure of blood to procoagulants generates intravascular coagulation. Compensatory hemostatic mechanisms are quickly overwhelmed, and as a result, a severe consumptive coagulopathy leading to hemorrhage develops. In contrast, chronic DIC reflects a compensated state that develops when blood is continuously or intermittently exposed to small amounts of procoagulants. Compensatory hemostatic mechanisms are not overwhelmed, and there may be little obvious clinical or laboratory indication of the presence of DIC.

Pathophysiology

Four simultaneous mechanisms seem to result in the hematologic derangements seen in DIC. They are TF (tissue factor)-mediated thrombin generation, dysfunctional physiologic anticoagulant mechanisms, impaired fibrin removal due to depression of the fibrinolytic system, and inflammatory activation.

Thrombin generation and tissue factor

Exposure to TF in the circulation occurs via endothelial disruption, tissue damage, or inflammatory or tumor cell expression of procoagulant molecules (including TF). TF activates coagulation by forming TF-VIIa complex which activates thrombin (the complex cleaves fibrinogen to fibrin while simultaneously causing platelet aggregaton), which is the extrinsic pathway of coagulant cascades. After produced by TF/factor VIIa pathway, thrombin amplifies both clotting and inflammation.

While the extrinsic pathway plays an important role in thrombin generation in DIC, the intrinsic pathway may also be activated in DIC, but it appears not to play an important role. The actual source of the TF has not been established with certainty. TF may be expressed on mononuclear cells in vitro, on polymorphonuclear leukocytes, on circulating monocytes of patients with severe infection, and on injured endothelial cells. Whereas, the  importance of the role TF expresson on injured endothelial play remains to be determined.

Impaired coagulation inhibitor systems

Thrombin generation is usually tightly regulated by multiple hemostatic mechanisms. However, once intravascular coagulation commences, compensatory mechanisms are overwhelmed or incapacitated. Impaired functioning of various natural regulating pathways of coagulation activation may amplify further thrombin generation and contribute to fibrin formation.

Three main substances consist the coagulation inhibitor systems including antithrombin, protein C, and TF pathway inhibitor (TFPI).

Usually patients with DIC have markedly reduced antithrombin level. The causation may be that antithrombin is continuously consumed by ongoing activation of coagulation, elastase produced by activated neutrophils degrades antithrombin, further antithrombin is lost to capillary leakage during DIC, and that production of antithrombin is impaired secondary to liver damage resulting from underperfusion and microvascular coagulation.

Protein C along with protein S, severs as a major anticoagulant compensatory mechanism. Under normal conditions, protein C is activated by thrombin when complexed on the endothelial cell surface with thrombomodulin. Activated protein C combats coagulation by proteolytic cleavage of factors Va and VIIIa and proteolyzes RAR1 when bound to the endothelial cell protein C receptor (EPCR). Impaired functioning of the protein C pathway is mainly due to down-regulation of thrombomodulin expression or its inactivation by cellular reactive oxygen species on endothelial cells by proinflammatory cytokines. Also the level of protein C is reduced during DIC as a result of continuously consumption, lost to capillary leakage and so on (similar to those described for antithrombin). So both low level and diminished activation of protein C result in the impaired anticoagulation function of coagulation inhibitor systems.

TF pathway inhibitor (TFPI) is another anticoagulant rechanism that is disabled in DIC. TFPI reversibly inhibits factor Xa and thrombin (indirectly) and has the ability to inhibit the TF-VIIa complex. During the DIC TFPI is relative insufficient which reduces the function of the coagulation inhibitor systems.

Defective fibrinolysis

The intravascular fibrin produced by thrombin is normally eliminated by a process termed fibrinolysis. Experimental models indicate that at the time of maximal activation of coagulation, the fibrinolytic system is largely shut off. Experimental bacteremia and endotoxemia result in a rapid increase in fibrinolytic activity, most probably caused by release of plasminogen activators from endothelial cells. However, this profibrinolytic response is almost immediately followed by suppression of fibrinolytic activity due to a sustained increase in plasma levels of PAI-1.

However, rare cases of DIC are characterized by a severe hyperfibrinolytic state on top of an activated coagulation system. Examples of such situations are the DIC that occurs as a complication of acute promyelocytic leukemia (APL/AML-M3) and some forms of adenocarcinoma. Clinically, these patients suffer from severe bleeding.

Inflammatory activation

Inflammatory and coagulation pathways interact in substantial ways. It is clear that there is cross-communication between the 2 systems, whereby inflammation gives rise to activation of the clotting cascade and the resultant coagulation stimulates more vigorous inflammatory activity. For example, thrombin produced by TF/factor VII pathway can amplify inflammation.

Screen Shot 2014-10-26 at 10.30.24 PMEtiology

Several disease states may lead to the development of DIC, generally via 1 of the following 2 pathways: 1. A systemic inflammatory response, leading to activation of the cytokine network and subsequent activation of coagulation (e.g., in sepsis or major trauma);2. Release or exposure of procoagulant material into the bloodstream (e.g., in cancer, crush brain injury, or in obstetric cases). These disease states include infections, maligancies, obstetric cases, transfusion related cases such as hemolytic reactions, trauma, and others.

Bacterial infection (in particular, bloodstream infection) is commonly associated with DIC. There is no difference in the incidence of DIC between patients with gram-negative and those with gram-positive sepsis. Systemic infections with other microorganisms, such as viruses and parasites, may lead to DIC as well. Factors involved in the development of DIC in patients with infections may be specific cell membrane components of the microorganism or bacterial exotoxins. These component cause a generalized inflammatory response, characterized by the systemic occurrence of proinflammatory of cytokines.

Table 1. Causes of Acute (Hemorrhagic) Disseminated Intravascular Coagulation

Type Cause
Infectious Bacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial) Viral (eg, HIV, cytomegalovirus [CMV], varicella-zoster virus [VZV], and hepatitis virus) Fungal (eg, Histoplasma)Parasitic (eg, malaria)
Malignancy Hematologic (eg, acute myelocytic leukemia) Metastatic (eg, mucin-secreting adenocarcinoma)
Obstetric Placental abruptionAmniotic fluid embolism Acute fatty liver of pregnancyEclampsia
Trauma Burns Motor vehicle accidents Snake envenomation
Transfusion Hemolytic reactions Transfusion
Other Liver disease/acute hepatic failure* Prosthetic devices Shunts (Denver or LeVeen)Ventricular assist devices
*Some do not classify this as DIC; rather, it is liver disease with reduced blood coagulation factor synthesis and reduced clearance of activate products of coagulation.

Prognosis

DIC may occur in 30-50% of patients with sepsis, and it develops in an estimated 1% of all hospitalized patients. The prognosis of DIC depends on the severity of the coagulopathy and on the underlying condition that led to DIC. However, assigning numerical figures to DIC-specific morbidity and mortality is difficult. In general, if the underlying condition is self-limited or can be appropriately handled, DIC will disappear, and the coagulation status will normalize. A patient with acute hemorrhagic DIC that is associated with metastatic gastric carcinoma likely has a lethal condition that does not alter patient demise, regardless of treatment. On the other hand, a patient with acute DIC associated with abruptio placentae needs quick recognition and obstetric treatment; the DIC will resolve with the treatment of the obstetric catastrophe.

Workup

Diagnosis of DIC can be difficult, especially in cases of chronic. Here we focus on acute DIC because it much worsen than chronic DIC with higher morbidity and mortality. The diagnosis of DIC relies on multiple clinical and laboratory determinations. The International Society on Thrombosis and Haemostasis (ISTH) developed a scoring system for the diagnosis of overt DIC that makes use of laboratory tests available in almost all hospital laboratories. The presence of an underlying disorder known to be associated with DIC (see Etiology) is a sine qua non for the use of this diagnostic algorithm. A score of 5 or higher indicates overt DIC, whereas a score of less than 5 does not rule out DIC but may indicate DIC that is not overt. Prospective validation studies show this scoring system to be highly accurate for the diagnosis of DIC. The sensitivity of the DIC score for a diagnosis of DIC is 91-93%, and the specificity is 97-98%.

Figure 1. Diagnostic Algorithm for The Diagnosis of Overt Disseminated Intravascular Coagulation

In clinical practice, a diagnosis of DIC can often be made by a combination of platelet count, measurement of global clotting times (aPTT and PT) and 1 or 2 clotting factors and inhibitors, and testing for FDPs.

Platelet count: typically, moderate-to-severe thrombocytopenia is present in DIC. Thrombocytopenia is seen in as many as 98% of DIC patients, and the platelet count can dip below 50 × 109/L in 50%. A decreasing treand in platelet counts or a grossly reduced absolute platelet count is a sensitive (though not specific) indicator of DIC. Repeated platelet counts are often necessary, a single platelet measurement may indicate a level within the normal range, whereas trend values might show a precipitous drop from previous levels.

Global clotting times: both aPTT and PT are typically prolonged. In as many as 50% of DIC patients, however, a normal or even an attenuated PT and aPTT may be encountered; consequently, such values cannot be used to exclude DIC. This phenomenon may be attributed to certain activated clotting factors present in the circulation, such as thrombin or Xa, which may in fact enhance thrombin formation.

It should be emphasized that serial coagulation tests are usually more helpful than single laboraatory results in establishing the diagnosis of DIC. It is also important to note that the PT, not the INR should be used in the DIC monitoring process. INR is recommended only for monitoring oral anticoagulant therapy.

DIC is associated with an unusual light transmission profile on the aPTT, known as a biphasic waveform. In one study, the degree of biphasic waveform abnormality had an increasing positive predictive value for DIC, independent of clotting time prolongation. In addition, the waveform abnormalities are often evident before more conventionally used laboratory value derangements, making this a quick and robust test for DIC.

Clotting factors: 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 factor VII.

Clotting inhibitors: protein C and antihrombin are 2 natural anticoagulants that are frequently decreased in DIC. There is some evidence to suggest that they may serve roles as prognostic indicators. Nonetheless, the practical application of measuring these anticoagulants may be limited for most practitioners the test may not generally available.

Fibrin: because fibrin is a central component of DIC, it would seem logical to assume that if soluble fibrin is elevated, the diagnosis of DIC can be made with confidence. However, soluble fibrin levels are not available to most clinicians within a relevant time fram.

Fibrinogen: the massive fibrin deposition in DIC suggests that fibrinogen levels would be decreased. Accordingly, measurement of fibrinogen has been widely advocated as a useful tool for the diagnosis of DIC; however, it is not, in fact, very helpful. Fibrinogen, as a positive acute-phase reactant, is increased in inflammation, and whereas values may decrease as the illness progresses, they are rarely low. On study demonstrated that in up to 57% of DIC patients, the levels of fibrinogen may in fact remain within normal limit.

Fibrin degradation products (FDPs): fibrinolysis is an important component of DIC; thus, there will be evidence of fibrin breakdown, such as elevated levels D-dimer and FDPs. D-dimer elevation means that thrombin has proteolyzed fibrinogen to form fibrin that has been cross-linked by thrombin-activated factor XIIIa. When fibrin becomes cross-linked insoluble, a unique D-D domain neoepitope forms. This cross-linked insoluble fibrin is then proteolyzed uniquely by plasmin to liberate the soluble D-D dimer. Thus, the D-dimer measures prior thrombin and plasmin formation. On the other hand, FDPs only inform that  plasmin has been formed and it cleaved soluble fibrinogen, fibrin, or insoluble cross-linked fibrin. D-dimer is the better test for DIC. However, FDPs are not used as often.

Thrombomodulin: This is the specialized test for DIC. Evidence suggests that serum levels of thrombomodulin, a marker for endothelial cell damage, correlate well with the clinical course of DIC, the development of multiple organ dysfunction syndrome (MODS), and mortality in septic patients. Thrombomodulin is elevated in DIC, and such elevation and not only correlates well with the severity of DIC but also can serve as a maker of early identification and monitoring of DIC.

Therapeutic Approach of Disseminated Intravascular Coagulation (DIC)

Treatment of DIC is controversial. Generally, the therapeutic approach consists of management of underlying disease, administration of blood components and coagulation factors, and restoration of anticoagulant pathways.

A DIC scoring system developed by Bick has been used to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities.[1] The scoring sytem is below (Table 2).

Table 2 Dic Scoring System by Bick

Parameter Finding Points
fibrinopeptide A in ng/mL < 3 0
3 – 10 1
11 – 40 2
41- 70 3
> 70 4
profragment 1,2 in nM 0.2 – 2.7 0
2.8 – 5.9 1
6.0 – 7.4 2
7.5 – 10.0 3
> 10.0 4
D-dimer µg/L < 500 0
500 – 1,000 1
1,001 – 2,000 2
2,001 – 2,999 3
>= 3,000 4
FDP (fibrin degradation products) in µg/mL < 10 0
10 – 40 1
41 – 80 2
81 –120 3
> 120 4
antithrombin (% of normal) 85 – 125% 0
75 – 84% 1
65 – 74% 2
54 – 64% 3
< 54% 4
alpha-2-antiplasmin (% of normal) 75 – 120% 0
65 – 74% 1
55 – 64% 2
45 – 54% 3
< 45% 4
fibrinogen in mg/dL 150 – 350 0
100 – 149 1
75 – 99 2
50 – 74 3
< 50 4
platelet count per µL 150,000 – 450,000 0
100,000- 149,999 1
75.000 – 99,999 2
50,000 – 74,999 3
< 50,000 4
temperature in °C <= 29.9 4
30 – 31.9 3
32 – 33.9 2
34 – 35.9 1
36 – 38.4 0
38.5 – 38.9 1
39 – 40.9 3
>= 41 4
mean arterial pressure in mm Hg <= 49 4
50 – 69 2
70 – 109 0
110 – 129 2
130 – 159 3
>= 160 4
pulse rate in beats/minute <= 39 4
40 – 54 3
55 – 69 2
70 – 109 0
110 – 139 2
140 – 179 3
>= 180 4
Parameter (cont.) Finding Points
respiratory rate per minute <= 5 4
6 – 9 2
10 – 11 1
12 – 24 0
25 – 34 1
35 – 49 3
>= 50 4
PaO2 in mm Hg 80 – 100 0
70 – 79 1
60 – 69 2
55 – 60 3
< 55 4
pH < 7.15 4
7.15 – 7.24 3
7.25 – 7.32 2
7.33 – 7.49 0
7.50 – 7.59 1
7.60 – 7.69 3
>= 7.70 4
creatinine in mg/dL < 0.6 2
0.6 – 1.4 0
1.5 – 1.9 2
2.0 – 3.4 3
>= 3.5 4
LDH in U/L <= 193 0
194 – 225 1
226 – 250 2
251 – 275 3
> 275 4
albumin in g/dL 3.5 – 5.5 0
3.0 – 3.4 1
2.6 – 2.9 2
2.1 – 2.5 3
<= 2.0 4
sodium in mEq/L <= 110 4
111 – 119 3
120 – 129 2
130 – 149 0
150 – 154 1
155 – 159 2
160 – 179 3
>= 180 4
potassium in mEq/L < 2.5 4
2.5 – 2.9 2
3.0 – 3.4 1
3.5 – 5.4 0
5.5 – 5.9 1
6.0 – 6.9 3
>= 7.0 4
hematocrit, in percent < 20 4
20 – 29.9 2
30 – 45.9 0
46 – 49.9 1
50 – 59.9 2
>= 60 4
total WBC count per µL < 1,000 4
1,000 – 2,999 2
3,000 – 14,999 0
15,000 – 19,999 1
20,000 – 39,999 2
>= 40,000 4

where:

• 0 points is assigned to normal findings

• mean arterial pressure = [(systolic pressure) + (2 × (diastolic pressure))] / 3

• Since LDH shows some variability between laboratories, the LDH range can be rewritten: 0 points (<= 100% upper limit of normal); 1 point (> 100% ULN – 117% ULN); 2 points (> 117% ULN – 130% ULN); 3 points (>130% ULN – 142% ULN); 4 points (> 142% ULN)

DIC score = 100 – SUM(points for all parameters)

DIC score Interpretation
>= 90 DIC unlikely
75 – 89 mild DIC
50 – 74 moderate DIC
< 49 severe DIC

Interpretation:

• maximum DIC score: 100

• minimum DIC score: 16

 

Underlying Disease

The management of DIC should primarily be directed at treatment of the underlying disorder. Often DIC component will resolve on its own with treatment. A DIC scoring system has been proposed by Bick to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities (Table 2).

Blood Components and Coagulation Factors

Typically, DIC results in significant reductions in platelet count and increases in coagulation times. However, platelet and coagulation factor replacement should not be instituted on the basis of laboratory results alone; such therapy is indicated only in patients with active bleeding and in those requiring an invasive procedure or who are otherwise at risk for bleeding complications.

Platelet transfusion may be considered in patients with DIC and severe thrombocytopenia, in particular, in patients with bleeding or in patients at risk for bleeding. The threshold for transfusion platelets varies. Most clinicians provide platelet replacement in nonbleeding patients if platelet counts drop below 20 × 109/L, though the exact levels at which platelets should be transfused is a clinical decision based on each patient’s clinical condition. In some instances, platelet transfusion is necessary at higher platelet counts, particularly if indicated by clinical and laboratory findings. In actively bleeding patients, platelet levels from 20 × 109/L to 50 × 109/L are grounds for platelet transfusion.

Previously, concerns have been expressed regarding the possibility that coagulation factor replacement therapy might “add fuel to the fire” of consumption; however, this has never been established in research studies.

It is generally considered that cryoprecipitate and coagulation factor concentrates should not routinely be used as replacement therapy in DIC, because they lack several specific factors (e.g., factor V). Additionally, worsening of the coagulopathy via the presence of small amounts of activated factors is a theoretical risk.

Specific deficiencies in coagulation factors, such as fibrinogen, can be corrected by administration of cryoprecipitate or purified fibrinogen concentrate in conjunction with fresh frozen plasma (FFP) administration.

Anticoagulation

Experimental studies have suggested that heparin can at least partly inhibit the activation of coagulation in cases of sepsis and other causes of DIC. However, a beneficial effect of heparin on clinically important outcome events in patients with DIC has not yet been demonstrated in controlled clinical trials. Moreover, antithrombin, the primary target of heparin activity, is markedly decreased in DIC, which means that the effectiveness of heparin therapy will be limited without concomitant replacement of antithrombin.

Furthermore, there are well-founded concerns with respect to anticoagulating DIC patients who are already at high risk for hemorrhagic complications. It is generally agreed that therapeutic doses of heparin are indicated in cases of obvious thromboembolic disease or where fibrin deposition predominates.

Restoration of Anticoagulant Pathways

The antithrombin pathway is largely depleted and incapacitated in acute DIC. As a result, several studies have evaluated the utility of antithrombin replacement in DIC. Most have demonstrated benefit in terms of improving laboratory values and even organ function. However, large-scale randomized trials have failed to demonstrate any mortality benefit in patients treated with antithrombin concentrate.

Activated protein C (APC) is an important regulator of coagulation. In studies of patients with sepsis who had associated organ failure, APC has been shown to reduce mortality and improve organ function. Protein C concentrate has been used to treat coagulation abnormalities in adult patients with sepsis. A study found protein C concentrate to be safe and useful in restoring coagulation and hematologic parameters; however further study is required.

Tissue factor pathway inhibitor (TFPI) has been shown very promising to arrest DIC and to prevent the mortality and end-organ damage in animal studies. However, a large phase III trial of TFPI in human with DIC did not show any mortality benefit. Recombinant thrombomodulin (rTM) can be used for treatment of DIC in cases of severe sepsis and hematopoietic malignancy. rTM not only allows the conversion of protein C to APC, but also inhibits the inflammatory process by interacting with high-mobility group B (HBGM-1). rTM has shown beneficial effects on DIC parameters and clinical outcome in initial trials, which it was found to yield significantly improved control of DIC in comparison with unfractionated heparin, particularly with respect to the control of persistent bleeding diathesis.

References

1. Rodger L. Bick. Disseminated Intravascular Coagulation: Objective Clinical and Laboratory Diagnosis, Treatment, and Assessment of Therapeutic Response. Semin Thromb Hemost 1996; 22(1): 69-88.