Disseminated intravascular coagulation
Disseminated intravascular coagulation (DIC) is the term most commonly used
for a clinicopathologic syndrome in which widespread intravascular coagulation is
induced by procoagulants that are introduced or produced in the blood circulation and
overcome the natural anticoagulant mechanisms. DIC may cause tissue ischemia from
occlusive microthrombi and bleeding from both the consumption of platelets and
coagulation factors and the anticoagulant effects of products of compensatory or
secondary fibrinolysis.
[Etiology]
Numerous disorders can provoke DIC: ①
Infections (Viral, bacterial,
rickettsial, mycotic, protozoal); ② Malignant diseases; ③ Obstetric complications
(Abruptio placentae, septic abortion and chorioamnionitis, amniotic fluid embolism,
intrauterine fetal death, miscellaneous); ④ Surgery and trauma ; ⑤ Miscellaneous
diseases.
[Pathogenesis]
The mechanisms that activate or “trigger” DIC act on processes that are
involved in normal hemostasis; namely, the processes of platelet adhesion and
aggregation and the contact-activated (intrinsic) and tissue-activated (extrinsic)
pathways of coagulation.
1. Activation of the extrinsic coagulation system by tissue factor expressed on cell
surfaces: trauma, cancer, obstetric events, ascites (shunt) etc;
2. Activation of intrinsic coagulation system by causing injury to endothelial cells:
hypotension, endotoxin, heat stroke, vasculitis, aneurysm, hemangioma etc;
3. Activation of coagulation factors, e.g., factor Ⅹ by cancers, factor Ⅱ by snake
venoms;
All of these lead to thrombin generation that in the presence of failure of the
control mechanisms results in intravascular coagulation. This in turn, can lead to
thrombosis and consumption of platelets, fibrinogen, and other coagulation factors.
Bleeding can be caused by depletion of these essential hemostatic components; by the
anticoagulant effects of fibrinogen/fibrin degradation products; and by further
depletion of fibrinogen, factor Ⅴ, and factor Ⅷ by plasmin if generated in excess
by the secondary fibrinolysis or if uninhibited due to diminished antiplasmin levels.
[Clinical features]
The manifestations of DIC depend on the magnitude and rate of exposure to the
DIC trigger. For example, the dramatic cases of “acute” DIC, characterized by severe
bleeding due to excessive consumption of hemostatic components, may develop when
blood is exposed to large amounts of tissue factor over a brief period of time.
Alternatively, “chronic” DIC develops when blood is continuously or intermittently
exposed to small amounts of tissue factor. Under these circumstances, clinical signs
may be minimal or altogether absent, and most coagulation tests will be only slightly
impaired.
1. Bleeding
Acute DIC is frequently heralded by hemorrhage into the skin at multiple sites.
Petechiae, ecchymosis, and oozing from veni-punctures, arterial lines, catheters, and
injured tissues are common. Bleeding may also occur on mucosal surfaces.
Hemorrhage may be life-threatening, with massive bleeding into the gastrointestinal,
lungs, central nervous system, or orbit. Patients with chronic DIC usually exhibit
minor skin and mucosal bleeding.
2. Thromboembolism
Extensive organ dysfunction can result from microvascular thrombi or from
venous and/or arterial thromboembolism. For example, involvement of the skin can
cause hemorrhage bullae, acral necrosis, and gangrene; involvement of the lungs can
cause acute respiratory distress syndrome, hypoxemia, edema, hemorrhage;
involvement of liver can cause jaundice, parenchymal damage; involvement of
gastrointestinal can cause bleeding, mucosal necrosis, and ulceration; involvement of
central nervous system can cause stupor, coma, convulsions, focal lesions and
intracranial bleeding.
3. Circulatory disturbance, shock
Both the diseases underlying DIC and DIC itself can cause shock. For example,
septicemia or excessive blood loss to trauma or to obstetric complications can by
themselves cause shock.
4. Microangiopathic hemolytic anemia
Erythrocytes are injured mechanically during passage through fibrin networks
in the microcirculation. Such microangiopathic hemolysis leads to the production or
schistocytes and microspherocytes.
[Laboratory features]
1. Basic blood examinations
(1) Platelet count: thrombocytopenia is an early and consistent sign of DIC.
(2) Peripheral blood smear: Examination of the blood smear reveals schistocytes in
approximately 50% of cases.
2. The coagulation defect
(1) Partial thromboplastin time (PTT), Prothrombin time, and thrombin time: The PTT,
PT, TT are prolonged in most patients with acute DIC. Early in the course of the
disorder, and in chronic DIC, the PTT may be normal, or even shorter than normal,
which may be the result of the procoagulant effects of activated coagulation factors.
(2) Fibrinogen concentration: The plasma levels of fibrinogen usually are significantly
depressed.
3. Tests for fibrinolysis
(1) Fibrinogen degradation products (FDP): There is usually an increased level of
FDP.
(2) D-dimer: Assay of plasma D-dimer is very useful for evaluation of patients with
DIC. Increased levels indicate that cross-linked fibrin generated by thrombin has been
digested by plasmin.
(3) Plasma protamine paracoagulation test (3P)
(4) Euglobulin lysis time
4. Other laboratory findings
(1) Fibrinopeptide A (FPA): FPA provide direct evidence of the action of thrombin on
fibrinogen, it is exceptionally sensitive indicators of DIC and may be normal even in
patients with normal levels of FDP.
(2) Antithrombin Ⅲ: Levels of antithrombin Ⅲ may be diminished in some cases.
(3) Factor Ⅷc levels
(4) Proteins C and S levels.
Laboratory data change with remarkable rapidity in DIC, and in doubtful cases, it
is often important to repeat the tests at frequent intervals, even every 8 to 12 hours
and observing the dynamics of the process.
[Differential diagnosis]
1. DIC and primary fibrinogenolysis.
2. DIC and severe liver disease.
[Treatment]
1. Management of underlying disorders
The survival of patients with DIC depends on vigorous treatment of the
underlying disorders and curtailing the triggers of blood coagulation. For example,
intensive
antibiotic
treatment
in
patients
with
gram-negative
bacteremia,
hysterectomy in patients with abruptio placenta, resection of an aortic aneurysm, and
debridement of crushed tissues are the most essential steps in the management of such
patients.
2. Heparin administration
Heparin is a specific activator of the physiologic antithrombin Ⅲ system and
thereby inhibits a number of proteolytic enzymes, including factors Ⅸa,Ⅹa and
thrombin.
Indications: Administration of heparin is beneficial in some categories of acute
and chronic DIC, including purpura fulminant, acute promyelocytic leukemia, dead
fetus syndrome (at time of removal), and aortic aneurysm (prior to resection). Heparin
is also indicated for treating thromboembolic complications in large vessels and
before surgery in patients with metastatic carcinoma. Heparin administration may also
be helpful when intensive blood component replacement fails to improve excessive
bleeding and fails to increase the level of hemostatic factors.
Dosage: The optimal dosage of heparin, however, is the source of some
disagreement. Good therapeutic responses have been documented even with minimal
dose regimens that do not significantly prolong the coagulation time, e.g., 5000 to
10000 U subcutaneously every 12 to 24 hours or 5 to 10 u/kg/hr by continuous drip.
Laboratory control of heparin therapy for DIC is difficult. A rough estimate of
the heparin level can be obtained from the coagulation time.
3. Antiplatelet drugs
Dipyridamole 200-400mg/d intravenous drip; Aspirin 0.9-1.2g/d; Low
molecular weight dextran 500-1500ml/d.
Indications: (1) in hypercoagulability state; (2) the diagnosis of DIC is still not
certain; (3) in mild cases.
4. Haemostatic support
In DIC the concentration of both procoagulant factors and their control protein
may be reduced. It is conventional offer haemostatic replacement therapy after
massive blood transfusion with: (1) platelet concentrates, 1 donor unit/10kg body
weight when the platelet count is below 50×109/L; (2) fresh frozen plasma (FFP)
10-15ml/kg body weight when the PTR is greater than 1.5; (3) additional
cryoprecipitate when the fibrinogen concentration is 0.8g/l or less.
5. Fibrinolytic inhibitors
Patients with early stage of DIC should not be treated by antifibrinolytic agents
like ε-aminocaproic acid and tranecamic acid. These drugs block the secondary
compensatory fibrinolysis that accompanies DIC and partially preserves tissue
perfusion.
In these conditions the use of fibrinolytic inhibitors can be considered, provided
that: (1) the patient is bleeding profusely and has not responded to replacement
therapy; (2)excessive fibrinolysis is observed, i.e., a very short euglobulin lysis time.
In such circumstances the use of antifibrinolytic agents should be preceded by
replacement of depleted blood components and continuous heparin infusion.