Disseminated Intravascular Coagulation DIC and APL

Dissseminated intravascular coagulation is not a disease or a symptom but a syndrome, which is always secondary to an underlying disorder. The syndrome is characterized by a systemic activation of the blood coagulation system, which results in the generation and deposition of fibrin, leading to microvascular thrombi in various organs and the development of multiorgan failure. Consumption and subsequent exhaustion of coagulation proteins and platelets because of the ongoing activation of the coagulation system may induce severe bleeding complications. Hence, a patient with DIC can present with a simultaneously occurring thrombotic and bleeding problem.

Many disease states may lead to the development of DIC. The most common diseases in patients with DIC are leukemia, infections, solid cancers, obstetric complications, and aortic aneurysm.15 In general there are two major pathways that may cause DIC: (1) a systemic inflammatory response, leading to activation of the cytokine network and subsequent activation of coagulation (such as in sepsis or major trauma) and/or (2) release or exposure of procoagulant material (in)to the bloodstream (such as in malignancies or in obstetrical cases). Procoagulant molecules include tissue factor (TF) and a cancer procoagulant, a cysteine protease with factor X-activating properties.8

Several simultaneously occurring mechanisms play a role in the pathogenesis of DIC:

(1) increased thrombin generation due to activation of the tissue factor/FVIIa pathway;

(2) dysfunctional anticoagulant pathways, including reduction in antithrombin and depression of the protein C system; and (3) impaired fibrinolysis, caused mainly by a sustained increase in plasma levels of PAI-1 (plasminogen activator inhibitor 1).

No single routinely available laboratory test is sufficiently sensitive or specific to enable a diagnosis of DIC. However, in clinical practice a diagnosis of DIC can often be made by a combination of platelet count, measurement of global clotting times [activated partial thromboplastin time (aPTT) and PT], measurement of one or two clotting factors and inhibitors (such as antithrombin), and a test for FDPs (fibrin degradation products). Serial coagulation tests are usually more helpful than single laboratory results in establishing the diagnosis of DIC. FDPs may be detected by specific enzyme-linked immunosorbent assays (ELISAs) or by latex agglutination assays. The main problem with these assays is low specificity since many other conditions such as inflammation or recent surgery are associated with elevated FDPs. More recently developed tests such as D-dimer, which are specifically aimed at the detection of neoantigens on degraded crosslinked fibrin, also suffer from low specificity.

To aid in diagnosis, a scoring system has been proposed by the ISTH (International Society of Thrombosis and Hemostasis). In the presence of an underlying disorder known to be associated with DIC, global coagulation tests are ordered (platelet count, PT, fibrinogen, FDPs). Using the results of these tests, a score is calculated that separates cases into overt DIC and nonovert DIC. The scoring system is a strong independent predictor of fatal outcome in intensive care patients. Some studies suggest that these traditional coagulation markers are not sensitive enough to diagnose nonovert DIC (or pre-DIC), which responds better to treatment than does overt DIC. Investigational hemostatic molecular markers include thrombin-antithrombin complex (TAT), prothrombin activation fragment F1 + 2, plasmin-plasmin inhibitor complex (PPIC), and aPTT biphasic waveforms, but these are not widely available and their clinical usefulness has not been proved.

The key of DIC treatment is the specific and forceful management of the underlying disorder. This may not always be sufficient, though, as DIC may proceed after proper treatment has been initiated, especially in patients with sepsis. Unfortunately, there are few scientifically validated treatment modalities for DIC. Supportive treatment is important, and plasma or platelet substitution therapy is indicated in patients with active bleeding and in those requiring an invasive procedure. Heparin has been used in the past, but a benefit has never been demonstrated in controlled clinical trials. Therefore, therapeutic doses of heparin are recommended only in patients with clinically overt thromboembolism or extensive fibrin deposition. One novel therapeutic agent, recombinant-human-activated protein C, has been shown to reduce mortality in patients with sepsis (with or without DIC) and is recommended in sepsis patients at high risk of death. Heparin should be withheld during administration of this drug.3

A life-threatening hemorrhagic diathesis consistent with DIC is present in 80-90% of APL patients at presentation and may be exacerbated by chemotherapy. It tends to be particularly severe in the microgranular variant of APL. Laboratory manifestations typical of DIC are typically present: low platelets, increased PT and aPTT, elevated fibrinogen degradation products (FDP), and decreased fibrinogen. Similar to other DIC conditions, there is laboratory evidence of both activation of the coagulation system and increase in fibrinolysis. One feature that distinguishes the coagulopathy of APL from typical DIC is the maintenance of relatively normal levels of the coagulation inhibitors antithrombin and protein C. The DIC is attributed to the spontaneous or chemotherapy associated release of a tissue factor with procoagulant activity present in the granules of the leukemic promyelocytes. In addition there is proteolysis due to release from the leukemic cells of lysosomal neutrophilic enzymes, including leukocyte elastase, which are able to cleave fibrinogen. APL cells also express high levels of annexin II, which is a fibrinolytic protein that increases the efficiency of plasmin formation. However, the role of primary fibrinolysis in the pathogenesis of DIC in APL is uncertain.2

Prior to the introduction of ATRA for the management of APL patients, fatal hemorrhage was a major cause of morbidity and mortality, thus contributing to failure of remission induction. In one large retrospective study the rate of early hemorrhagic deaths was about 10% and this was not affected by treatment with either heparin or antifibrinolytic drugs.9 ATRA rapidly reverses the coagulopathy in most patients with APL, so ATRA therapy should be started as soon as possible. Some have suggested that ATRA should be given as soon as APL is suspected, instead of waiting for genetic confirmation of diagnosis, because a fraction of patients develop fatal hemorrhages during the diagnostic evaluation before beginning antileukemic therapy or during the first days of induction. In a 2001 multicenter study of patients receiving ATRA for induction therapy, mortality due to early hemorrhage was about 5%.11 Therefore, rapid institution of supportive measures to reverse the coagulopathy may lower the risk of life-threatening hemorrhages in these patients. Treatment should be based on liberal transfusion of fresh-frozen plasma, fibrinogen, or both, as well as on aggressive platelet support to maintain the fibrinogen level above 150 mg/L and the platelet counts above 30-50 x 109/L until clinical signs of coagulopathy have disappeared.13

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