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Learning Center
Coagulation Corner
Monday, August 2, 2010
BIOMARKERS OF COAGULATION: What, when and where?
Last month the coagulation community lost a dedicated colleague and a friend. JoAnn Carabello ran the special coagulation laboratory at Temple University. She was also responsible for organizing the annual Temple Coagulation Symposium, which was responsible for educating and updating so many technologists and clinicians on relevant coagulation topics. She will be missed. Please remember her in your prayers. This is dedicated to her.
BIOMARKERS OF COAGULATION: What, when and where?
What is a biomarker- a biomarker is defined as a parameter that is measureable, reflects disease, is reproducible and will be affected by treatment. Biomarkers are biological indicators that have been associated with disease. Certain markers of inflammation, blood clotting, and blood vessel function have been associated with risk of cardiovascular disease, stroke and death. For example, markers of inflammation include: C-reactive protein (CRP), fibrinogen and white blood cells (WBC), with CRP being the most sensitive. It is also known that fibrinogen is an independent risk marker for an MI, higher than elevated cholesterol. It must be determined that the elevated fibrinogen is not a result of an acute phase reactant and is truly a hereditary persistence of an elevated fibrinogen.
Other biomarkers of coagulation include:
Prothrombin time (PT), activated partial thromboplastin time (APTT), and D-dimer, protein C, protein S, and antithrombin, IL-6 , prothrombin fragment F1.2 (F1.2), thrombin–antithrombin complex (TAT), plasminogen activator inhibitor (PAI)-1, thrombin activatable fibrinolysis inhibitor (TAFI), α2-antiplasmin (α2-AP), plasminogen, and soluble thrombomodulin (sTM).
Biomarkers and Sepsis:
In patients with sepsis the coagulopathy is more reflective of activation of coagulation and thrombin generation than of impaired fibrinolysis. Thrombin generation markers TAT and F1.2 are present in most patients versus TAFI, which is an acute phase reactant. The more severe septic patients (higher APACHE scores) may also prevent with elevated baseline D-dimers, PT, APTT, PAI-1, sTM versus decreased PC, PS and AT. A global improvement in coagulation markers has been observed in survivors as compared with nonsurvivors. Markers of ongoing thrombin generation, TAT, F1.2, and D-dimer, improved more rapidly in survivors than in nonsurvivors over time. Of the 13 coagulation markers that correlated with disease severity, PT may be the most clinically useful. Consumption and depletion of endogenous hemostasis factors occurs frequently in patients with severe sepsis, as shown in this and other studies, and may occur before the clinical diagnosis of the first sepsis-associated acute organ dysfunction. The PT is a marker that is easily and readily measurable in most clinical settings.
Coagulation Biomarkers and HIV:
More than 30 million people are infected with the human immunodeficiency virus(HIV), the virus that causes acquired immunodeficiency syndrome (AIDs, HIV infects and destroys immune system cells (including CD4 cells, a type of lymphocyte). The immune system becomes so damaged that HIV-infected individuals begin to succumb to “opportunistic” infections (for example, bacterial pneumonia) and cancers (in particular, Karposi sarcoma) that the immune system would normally prevent. HIV infections cannot be cured but antiretroviral therapy (ART)—combinations of powerful antiretroviral drugs—can keep them in check, so many HIV positive people now have substantially improved life expectancy.
A study looked at the frozen blood samples of patients who had died from HIV. Levels of proteins that indicate the presence of inflammation or increased coagulation (biomarkers) were measured. In this study, an increased risk of death was associated with higher levels at study entry of the inflammation biomarkers high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6) and of the coagulation biomarker D-dimer. The risk of death among people with hsCRP values in the highest quarter of measured values was twice that among people with hsCRP values in the lowest quarter with an odds ratio of 2. For IL-6 and D-dimer, the equivalent odds ratios were 8.3 and 12.4, respectively. Increases in hsCRP, IL-6 and D-dimer after study entries were associated with an increased risk of death. The findings suggest that HIV-induced activation of inflammation and coagulation increases the risk of death among HIV-positive patients and that interrupting ART further increases this risk, possibly by increasing IL-6 and D-dimer levels. These findings suggest that the development of therapies that reduce the effect that HIV replication has on inflammation and blood coagulation, or that reduce IL-6 and D-dimer levels, might extend the life-expectancy of HIV-positive people.
Coagulation Biomarkers and Cardiovascular Disease:
Inflammation plays a major role in the development and progression of atherosclerosis, including plaque rupture which initiates coronary thrombosis and myocardial infarction (MI) .Activated coagulation, endothelial dysfunction and fibrinolysis have also been associated with risk of coronary heart disease (CHD)
The term CHD covers all forms of atherosclerotic disease of the coronary arteries with MI/coronary death as the most serious manifestation and with angina (unstable or stable) as a specific symptom complex indicating myocardial ischemia. Many studies have shown independent associations between CHD events (MI and CHD death) and C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen, von Willebrand factor (VWF), fibrin D-dimer and tissue plasminogen activator antigen (t-PA) in both middle-aged and older populations.
The major pathophysiological difference distinguishing MI and other acute coronary syndromes from uncomplicated stable angina pectoris is the rupture of an atherosclerotic plaque with subsequent thrombosis formation, which causes acute coronary events.
A study looked at the relationship between inflammatory and hemostatic biomarkers including CRP, IL-6 plasma viscosity and several markers of activated coagulation, fibrinolysis and endothelial dysfunction [fibrinogen; coagulation factors VII, VIII, and IX; fibrin D-dimer, t-PA antigen, VWF activated partial thromboplastin time (APTT) and activated protein C (APC) ratio]. The results concluded that this relationship differed between older men aged 60–79 years who develop (i) incident MI or CHD death and (ii) incident stable angina, uncomplicated by MI or CHD death. Circulating biomarkers of inflammation and hemostasis are associated with incident MI/CHD death but not incident angina uncomplicated by MI or CHD death in older men.
Inflammatory Bowel Disease and Coagulation BIomarkers
Inflammatory bowel disease (IBD) as a chronic inflammatory condition characterized by a hypercoagulable state and prothrombotic conditions. A study evaluated the abnormalities in coagulation and fibrinolysis status in patients with IBD, and to analyze parameters of altered coagulation and fibrinolysis status which can correlated with and predict inflammatory parameters of disease activity. IBD patients were compared with healthy controls for coagulation and fibrinolysis status. Associations between altered coagulation and fibrinolysis status stratified by gender and inflammatory parameters were analyzed. The mean levels of platelet, platelet distribution width, prothrombin time, fibrinogen, activated partial thromboplastin time were significantly higher in IBD patients than in healthy controls (all P<0.05). Mean platelet volume was lower in male patients with IBD than in healthy controls (P<0.01). Furthermore, multiple linear regression indicated that fibrinogen was an independent predictor of ESR (β=1.316, P=<0.001) and CRP (β=1.233, P=0.015) in male patients with active ulcerative colitis. Platelet (β=0.436, P=0.037) and prothrombin time (β=0.810, P=<0.001) were predictors of Crohn's Disease Activity Index in female patients with Crohn's disease. This study provides characteristics on altered coagulation and fibrinolysis status in active IBD patients. The data suggest that in IBD patients, abnormalities in coagulation and fibrinolysis status were associated with disease activity. Fibrinogen, platelet and prothrombin time were predictors of inflammation.
Conclusion:
Biomarkers play an important role in the diagnosis and management of disease. Identifying coagulation biomarkers and their presence in certain disease states may aid in predicting treatment modalities and rate of survival.
Donna D. Castellone
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About the Author
Donna Castellone,
MS, MT(ASCP)SH
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