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Key Event Title
Thrombosis and Disseminated Intravascular Coagulation
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|SARS-CoV2 to thrombosis and DIC||AdverseOutcome||Shihori Tanabe (send email)||Under development: Not open for comment. Do not cite|
|Sars-CoV-2 causes stroke||KeyEvent||Magda Sachana (send email)||Under development: Not open for comment. Do not cite|
|Homo sapiens||Homo sapiens||Moderate||NCBI|
|All life stages||Not Specified|
Key Event Description
Thrombosis is defined as the formation or presence of a thrombus. Clotting within a blood vessel may cause infarction of tissues supplied by the vessel. Extreme aggravation of blood coagulation induces multiple thrombi in the microvasculature, which leads to consumption coagulopathy followed by disseminated intravascular coagulation (DIC).
DIC is a pathological syndrome resulting from the formation of thrombin, subsequent activation and consumption of coagulation proteins, and the production of fibrin thrombi. The initial pathologic events are thrombotic in nature resulting in thrombotic vascular occlusions. The initial clinical events are usually hemorrhagic resulting in oozing from mucosa and massive gastrointestinal blood loss. The occlusive events occur as a result of fibrin microthrombi or platelet microthrombi that obstruct the microcirculation of organs. This obstruction can result in organ hypoperfusion and ischemia, infarction, and necrosis. All organs are potentially vulnerable to the effects of thrombotic occlusions.
The renal effects of DIC are multifactorial and may be associated with hypovolemia or hypotension. If the hypotension is not corrected it may lead to renal failure due to acute tubular necrosis. Fibrin thrombi may also block glomerular capillaries causing ischemic, renal cortical necrosis (Colman, 1984).
The cerebral effects of DIC often result in nonspecific changes such as altered state of consciousness, convulsions, and coma. Major vascular occlusions, subarachnoid hemorrhage, multiple cortical and brain stem hemorrhages may occur following microvascular occlusions (Schwartzman RJ, 1982).
The pulmonary effects of DIC may be caused by interstitial hemorrhage resulting in a clinical effect resembling acute respiratory distress syndrome (Schwartzman RJ,1973; Shahl RL, 1984).
How It Is Measured or Detected
Clinical laboratory tests are used to diagnose DIC.
Prothrombin time (PT) is a blood test that measures how long it takes blood to clot. PT measures the time required for fibrin clot formation after the addition of tissue thromboplastin and calcium. The average time range for blood to clot is about 10 to 13 seconds.
Activated partial prothrombin time (APTT). Platelet poor plasma [PPP] is incubated at 37°C then phospholipid (cephalin) and a contact activator (e.g. Kaolin, micronized silica, or ellagic acid) are added. This leads to the conversion of Factor XI [FXI] to FXIa. The remainder of the pathway is not activated as no calcium is present. The addition of calcium (pre-warmed to 37°C) initiates clotting. The APTT is the time taken from the addition of calcium to the formation of a fibrin clot. The clotting time for the APTT lies between 27-35 seconds.
Decreased fibrinogen concentrations
Diluted plasma is clotted with a high concentration of Thrombin. The tested plasma is diluted (usually 1:10 but this may vary if the Fibrinogen concentration is very low or very high) to minimize the effect of 'inhibitory substances' within the plasma e.g. heparin, elevated levels of FDPs. The use of a high concentration of Thrombin (typically 100 U/ml) ensures that the clotting times are independent of Thrombin concentration over a wide range of Fibrinogen levels. The test requires a reference plasma with a known Fibrinogen concentration and that has been calibrated against a known international reference standard. A calibration curve is constructed using this reference plasma by preparing a series of dilutions (1:5 –1:40) in the buffer to give a range of Fibrinogen concentrations. The clotting time of each of these dilutions is established (using duplicate samples) and the results (clotting time(s)/Fibrinogen concentration (g/L) are plotted on Log-Log graph paper. The 1:10 concentration is considered to be 100% i.e. normal. There should be a linear correlation between clotting times in the region of 10-50 sec. The test platelet-poor diluted plasma (diluted 1:10 in buffer) is incubated at 37°C, Thrombin [~100 U/mL] added (all pre-warmed to 37°C). The time taken for the clot to form is compared to the calibration curve and the Fibrinogen concentration deduced. Test samples whose clotting times fall out with the linear part of the calibration curve should be re-tested using different dilutions. Most laboratories use an automated method in which clot formation is deemed to have occurred when the optical density of the mixture has exceeded a certain threshold.
A platelet count is the number of platelets a person has per microliter. The ideal platelet range is 150,000 – 400,000 per microliter in most healthy people.
d-dimer concentration ALERE TRIAGE® D-DIMER TEST
D-Dimer can be measured by a fluorescence immunoassay. To determine cross-linked fibrin degradation products containing D-dimer in EDTA anticoagulated whole blood and plasma specimens. The test is used as an aid in the assessment and evaluation of patients suspected of having disseminated intravascular coagulation or thromboembolic events including pulmonary embolism
Commercially available kits are available to measure d-dimer in whole blood or plasma. The kits contain all the reagents necessary for the quantification of cross-linked fibrin degradation products containing D-dimer in EDTA anticoagulated whole blood or plasma specimens.
Domain of Applicability
Evidence for Perturbation by Stressor
Regulatory Significance of the Adverse Outcome
Thrombosis is one of the world’s main concerns in terms of severe symptoms or adverse responses of the vaccine for COVID-19 which is caused by SARS-CoV-2. Excess thrombosis leads to DIC, which might be mortal. For safely developing the therapeutics and vaccines of COVID-19, it is regulatory significant to understand the cellular and molecular mechanisms in the pathogenesis of coronaviral infection, which may include thrombosis and DIC, AO1846.
Hemostasis and Thrombosis Basic Principles and Clinical Practices Robert W Colman, Jack Hirsh, Victor J. Marder, Edwin W. Salzman (ed) Philadelphia, 1994.
Schwartzman RJ, Hill JB: Neurologic complications of DIC. Neurology 32:791, 1982
Robboy SJ, Minna JD, Colman RW et.al. Pulmonary hemorrhage syndrome as a manifestation of DIC: Analysis of 10 cases. Chest 63:718, 1973.
Stahl RL, Javid JP, Lackner H: Unrecognized pulmonary embolism presenting as DIC. SM J Med 76:772, 1984.