- Cell-based coagulation model
- Traditional tests of enzymatic coagulation
- Thromboelastography (TEG)
- Platelet dysfunction in critical illness
- Questions & discussion
cell-based coagulation model
All models are wrong, but some are useful. –George Box
Coagulation is an enormously complex process involving dozens of factors and numerous cell types – all occurring within the dynamic context of flowing blood. A perfect model for this process doesn't exist. Traditionally, our understanding of coagulation has been based on a severely reductionist approach involving solely clotting factors (figure below).
This two-pathway coagulation model is inexorably linked to traditional coagulation tests (INR and PTT). However, reality is far more complex than this. For starters, coagulation factors participate in dynamic auto-amplifying loops (see green arrows below). Thus, rather than being a linear process, coagulation involves cyclical amplification.
The next level of complexity involves understanding how coagulation factors interact with cellular elements. Traditional coagulation assays begin by separating out the cellular components of blood via centrifugation and throwing the cells away. However, coagulation factors interact with cells in critical ways. Therefore, the most accurate model of coagulation will take these interactions into account (i.e., a cell-based coagulation model).(30711233) This model still requires understanding coagulation factors, but takes this understanding to the next level by mapping the activation of coagulation factors onto cells. For example, cellular activation may change its expression of phospholipids, facilitating the binding of coagulation factors. Current cell-based coagulation models divide coagulation into roughly three phases:
#1 initiation phase
- Coagulation is initiated by the expression of tissue factor (TF) on the cell. The cells involved at this phase are often connective tissue cells that are not normally exposed to the bloodstream (e.g., fibroblasts, vascular smooth muscle cells). During hemorrhage, blood comes into contact with these cells, initiating coagulation.
- Tissue factor promotes the activation of factors VIIa, Xa, Va, and IIa. This generates thrombin via the tissue factor (extrinsic) pathway.
- Any activated factor Xa which dissociates from the cell membrane will be rapidly inactivated by tissue factor pathway inhibitor (TFPI) or antithrombin. Thus, thrombin generation is localized to the surface of the tissue factor-bearing cell.
#2 amplification phase
- Some thrombin (factor IIa) binds to nearby platelets, resulting in platelet activation. Platelet activation has numerous consequences:
- Activation stimulates the release of platelet granules, which contain numerous procoagulant substances.
- Platelet activation triggers changes in the platelet membrane phospholipids, producing a procoagulant membrane surface on the platelets.
- Thrombin on the platelet surface starts to generate some activated coagulation factors:
- Thrombin cleaves XI to XIa
- Thrombin cleaves V to Va
- Thrombin cleaves the vWF-VIII complex, yielding activated VIIIa and free vWF. The free vWF (von Willebrand factor) mediates platelet adhesion and aggregation.
#3 propagation phase
- Additional platelets are recruited, due to platelet granule release and vWF activity.
- XIa activates the intrinsic pathway, leading to further activation of thrombin. This leads to a cyclical auto-amplifying loop involving factors XI, IX, X, V, and II (the intrinsic clotting pathway). This results in the generation of lots of thrombin (known as a “thrombin burst”).
- Large amounts of thrombin (IIa) lead to fibrin generation and clot formation.
traditional tests of enzymatic coagulation
The coagulation cascades are shown above, along with common tests that investigate specific portions of the cascade. Please note that these cascades are useful for diagnostic purposes, especially for identifying patients with single-factor deficiency (e.g., hemophilia). However, these labs don't correlate well with clinical bleeding in patients with complex coagulopathies (e.g., cirrhosis, DIC).
prolongation of INR with normal PTT
physiology and general comments
- Isolated INR prolongation often indicates factor VII deficiency, as this is the factor involved in INR but not PTT (figure above). However, mild deficiencies in common pathway proteins (factor X, V, II, or fibrinogen) can also cause predominant abnormalities in the INR.
- INR prolongation correlates with clinical clotting in patients on warfarin. However, INR prolongation does not correlate well with bleeding among patients with liver disease or DIC (who often have numerous coagulation abnormalities, including deficiencies of endogenous anticoagulants, such as proteins C and S).
- INR represents a method of standardizing PT (prothrombin time) values across different laboratories. The clinical significance of INR and PT prolongation are identical. INR is preferred over PT, since this is more reproducible and more easily interpreted.
differential diagnosis of INR elevation with normal PTT
- If INR corrects one day after IV vitamin K:
- Vitamin K deficiency (not uncommon in ICU, especially among chronically critically ill patients).
- If INR doesn't correct one day after IV vitamin K:
- Liver disease (cirrhosis or acute liver failure).
- Factor Xa inhibitors (e.g., riveroxaban, apixaban).
- Severe lupus anticoagulant.
- Factor VII inhibitor (extremely rare).
- Mild, nonspecific elevation (ICU patients often have elevations in the ~1.2-1.6 range, of no clinical significance). (DeLoughery 2019)
intravenous vitamin K challenge
- 10 mg of IV vitamin K may be used as a therapeutic and diagnostic approach, to help understand the cause of INR prolongation.
- If vitamin K administration results in INR reduction, this reveals and treats vitamin K deficiency or warfarin effect.
- If vitamin K administration doesn't normalize the INR (or incompletely normalizes the INR), this excludes the presence of isolated vitamin K deficiency.
- Vitamin K must be given intravenously (rather than orally) to exclude the possibility of malabsorption. More discussion about the administration of intravenous vitamin K here.
prolonged PTT with normal INR
physiology and general comments
- Isolated PTT abnormalities often reflect deficiencies of factors XII, XI, IX, or VIII (as these are unique to the intrinsic activation pathway; see figure above).
- Deficiency of factors XII or XI may elevate PTT without causing a substantial clinical coagulopathy. These factors are involved in laboratory measurement of PTT, but are less important for in vivo clotting.
- Elevated levels of factor VIII may shorten the PTT. This is most often seen in inflammatory states, but also in pregnancy, uremia, and in patients on cyclosporine.(DeLoughery 2019) Elevated levels of VIII may lead to heparin or argatroban pseudoresistance (discussed further here).
- Only ~50% of most coagulation factors are required to generate normal-range coagulation labs. Therefore, if PTT elevation is simply due to a factor deficiency, then mixing the patient's plasma with normal plasma in a 1:1 ratio should lead to a mixture with normal PTT values.
- If the PTT elevation is caused by a factor inhibitor (e.g., neutralizing antibodies or lupus anticoagulant), then mixing with normal plasma in a 1:1 ratio will not result in a mixture with normal PTT values.
- Mixing studies may be used to parse out the causes of PTT elevation as below.
differential diagnosis of isolated PTT elevation
- PTT corrects with mixing: Deficiency of factors XII, XI, IX, or VIII.
- Hemophilia A (factor VIII deficiency)
- Severe von Willebrand disease with factor VIII deficiency
- Hemophilia B (factor IX deficiency)
- Factor XI deficiency (minimally symptomatic)
- PTT fails to correct with mixing:
- Unfractionated heparin (including heparin contamination). Note that low-molecular-weight heparin often doesn't affect the PTT, so it may not be detected by standard coagulation assays.
- Lupus anticoagulant (will correct if exogenous phospholipid is added).
- Acquired inhibitor of factor VIII, IX, or XI.
- (PTT elevation may also result from artifact; in one series 14% of PTT elevations were simply artefactual)(32685885)
prolongation of both INR and PTT
physiology and general comments
- Prolongation of both INR and PTT suggests a deficiency of the factors shared in both pathways (factors X, V, II, and fibrinogen).
- Global aberrations in the coagulation system will tend to affect both INR and PTT (e.g., DIC).
differential diagnosis of INR & PTT elevation
- More common:
- Severe warfarin effect or vitamin K deficiency.
- Severe liver dysfunction.
- Medication effect:
- Direct thrombin inhibitor (e.g., argatroban, dabigatran).
- High level of unfractionated heparin.
- Extremely low fibrinogen (below ~80 mg/dL). Note that a normal PT and INR don't exclude hypofibrinogenemia.
- Less common:
- Lupus anticoagulant, severe.
- Rare deficiency or inhibitor involving factors V, X, or II.
- Elevated fibrinogen degradation products (following thrombolysis).
- Massive hemorrhage with dilution of coagulation factors.
- Factor X deficiency associated with systemic amyloidosis.(32685885)
approach to elevated INR & PTT of unclear etiology
- Review the medication list (look for any thrombin inhibitors or heparin).
- Check fibrinogen and D-dimer levels (to evaluate for hypofibrinogenemia or DIC).
- Check liver function tests.
- If vitamin K deficiency or warfarin are a possibility, a diagnostic/therapeutic challenge with IV vitamin K could be considered.
thrombin time & fibrinogen level
- Both of these tests involve the addition of activated thrombin to the patient's plasma. The assays evaluate the ability of the thrombin to catalyze polymerization of fibrinogen.
- Thrombin time involves the use of undiluted plasma.
- This renders the thrombin time more sensitive to inhibitors (e.g., heparin).
- Thrombin time will also be prolonged by absent or dysfunctional fibrinogen.
- The Clauss assay for fibrinogen involves the use of diluted plasma.
- This dilutes out inhibitors (e.g., heparin), allowing the Clauss assay to focus more on fibrinogen function.
- Although the Clauss assay is typically referred to as a “fibrinogen level,” it is actually an assay of fibrinogen function.
differential diagnosis of low fibrinogen (using the Clauss fibrinogen assay)
- Liver disease.
- Dilution following massive transfusion.
- Following administration of a thrombolytic agent.
- Malignancy or cirrhosis (i.e., Accelerated Intravascular Coagulation and Fibrinolysis).
- Inherited fibrinogen abnormalities (e.g., hypofibrinogenemia, dysfibrinogenemia).
differential diagnosis of a prolonged thrombin time
- (1) Any cause of low fibrinogen (see list immediately above 👆).
- (2) Inhibitor substances (these will not affect the Clauss fibrinogen assay very much, although high levels of unfractionated heparin may cause some reduction in the Clauss fibrinogen level.)
- Medications inhibiting thrombin:
- Direct thrombin inhibitor (e.g., argatroban, dabigatran).
- High level of unfractionated heparin.
- Elevated fibrinogen degradation products (following thrombolysis).
- Medications inhibiting thrombin:
clinical utilization of thrombin time versus Clauss fibrinogen assay
- Thrombin time and fibrinogen provide relatively similar information.
- Thrombin time is less widely available and has a slower turn-around time. Therefore, fibrinogen is more widely utilized clinically. Fibrinogen is also a more actionable laboratory study, with defined transfusion targets.
strengths and weaknesses of TEG
strengths of the TEG (thromboelastography)
- TEG provides a more integrative evaluation of coagulation, which allows evaluation of the interaction of coagulation factors, endogenous anticoagulants, and cellular elements.
- TEG allows evaluation of platelet function, whereas traditional coagulation laboratories merely monitor the platelet count.
- TEG can account for the balance of coagulation, taking into account both clotting factors and endogenous anticoagulant proteins (e.g., antithrombin III).
- TEG allows evaluation of thrombolysis, which isn't measurable using conventional coagulation assays.
- TEG allows rapid testing of the effects of heparin on coagulation. This isn't possible using conventional studies available at most hospitals.
- TEG allows clinicians to avoid the practice of focusing on the INR, with subsequent use of plasma in efforts to normalize the INR. Avoidance of INR-driven blood product usage might be the single greatest advantage of using TEG. When compared to using platelet counts, using TEG as a trigger for platelet transfusion may likewise reduce platelet transfusion.(33089934)
- TEG may achieve faster turn-around times than conventional coagulation laboratories. Many hospitals have online portals which allow clinicians to see the TEG tracing as it occurs in real time.
weaknesses of TEG
- Standard TEG doesn't typically measure most antiplatelet drug effects (e.g., aspirin, clopidogrel, etc.). Detection of these medications requires a specific platelet mapping study.
- The low-shear conditions under which TEG occurs result in so much thrombin generation that most platelet-activation pathways are unnecessary. Thus, TEG is insensitive to antiplatelet medications other than glycoprotein IIb/IIIa inhibitors.(33089939)
- TEG isn't sensitive for detecting DOACs (e.g., riveroxiban, apixiban, dabigatran).
- TEG is insensitive to many other coagulation abnormalities:
- von Willebrand disease.
- Deficiencies in antithrombin-III, protein C, protein S, or factor V Leiden.
- Effects of hypothermia (the assay is performed at 37 degrees Centigrade).
- Hypocalcemia will be overlooked (because exogenous calcium is added to the sample).
- TEG is not able to pinpoint the diagnosis of uncommon coagulation abnormalities (e.g., differentiate factor VII deficiency versus factor VIII deficiency).
situations where TEG is most useful
- TEG is most helpful in complex coagulopathies where multiple coagulation abnormalities are occurring simultaneously:
- DIC, including trauma-induced coagulopathy.
- Complex intraoperative coagulopathies (e.g., cardiothoracic surgery, liver transplant surgery).
- Extracorporeal membrane oxygenation (ECMO).
- TEG is less useful to investigate a simple coagulation question:
- Coagulation status of an uncomplicated patient on coumadin (INR works just fine).
- Coagulation status of an uncomplicated patient on heparin (PTT or anti-Xa level is fine).
TEG yields a multitude of parameters. These parameters tend to be overinterpreted, in ways which are not evidence-based. Most notably, the alpha-angle is often touted to be a reflection of fibrinogen function. This seems to be a myth: the alpha-angle is actually a reflection of both the fibrinogen and platelet functions.(26197367) In order to truly determine the fibrinogen function, a more specialized TEG assay is required (a functional fibrinogen assay that includes abciximab, in order to eliminate platelet function and solely elucidate the fibrinogen activity alone).
If we can ignore the redundant and non-evidence-based parameters, interpretation of the TEG is easier. There are really just a few key pieces of information:
reaction time (R-time)
- This measures the time lag until clotting begins, following the addition of kaolin (a contact activator which triggers the intrinsic pathway).
- R-time is a measurement of enzymatic coagulation via the intrinsic pathway (most analogous to PTT).
- Prolonged R-time in a bleeding patient indicates hypocoagulability. This may trigger the administration of fresh frozen plasma or prothrombin product concentrates (PCC).
- Normal R-time reveals intact enzymatic coagulation. Such patients are unlikely to benefit from the administration of fresh frozen plasma (FFP). Finding a normal R-time can be an enormously useful finding in patients with cirrhosis or DIC who have an elevated INR and/or PTT – who might otherwise tend to be transfused with fresh frozen plasma.
- Reduced R-time may suggest hypercoagulability, with an increased risk of thromboembolic complications.(31263903)
- If the R-time is prolonged (revealing enzymatic hypocoagulation), the lab will reflexively perform a TEG with heparinase (which eliminates the effect of heparin).
- If the R-time of the second TEG (the “heparinase TEG”) is >25% lower than the initial TEG (the “native TEG”), this indicates the presence of a heparin effect.
- Heparin effect may be caused by exogenous or endogenous heparins:
- Exogenous heparins are therapeutically administered to the patient (including unfractionated heparin or low-molecular-weight heparin).(28267938)
- Endogenous heparins are generated by the patient, due to degradation of the endothelial glycocalyx (which contains heparins). Presence of endogenous heparins (“autoheparinization”) is very worrisome, as it often reflects severe inflammation or endothelial damage.
maximum amplitude (MA)
- This is the maximal clot strength. It reflects the combined function of fibrinogen and platelets.
- Low MA in a bleeding patient may suggest benefit from platelet and/or fibrinogen transfusion. The choice of platelets versus fibrinogen may depend on the clinical context:
- Traditional laboratory testing (e.g., complete blood count and/or fibrinogen levels) may help determine which is more deficient. Likewise, a more specialized TEG assay (e.g., TEG functional fibrinogen) may help sort this out.
- When in doubt, use of fibrinogen may be preferable, as fibrinogen is consumed more slowly than platelets and may pose fewer risks than platelet transfusion. Critically ill patients (especially those with cirrhosis) may tend to rapidly consume platelets, rendering platelet transfusion difficult or unsustainable. Furthermore, even in the presence of thrombocytopenia, administration of fibrinogen may still improve the MA.(19224779) Some studies have found that using fibrinogen as a front-line therapy for maintaining an adequate maximum amplitude was associated with reduced blood loss.(28267938)
lysis in 30 minutes (LY30)
- LY30 reflects the degree of clot breakdown over thirty minutes. Unfortunately, standard TEG assays are rather insensitive to hyperfibrinolysis.(33089934) Thus, a normal LY30 doesn't exclude hyperfibrinolysis. Most studies and clinicians define an abnormal LY30 as over ~3%. (31263903)
- Elevated LY30 suggests hyperfibrinolysis. In the context of clinical hemorrhage, this suggests benefit from a fibrinolytic inhibitor (e.g., tranexamic acid).
- No clot lysis at all (i.e., LY30 = 0) may suggest a situation where fibrinolysis is inhibited (a.k.a., “fibrinolytic shutdown”), which might increase the risk of thrombosis. However, this is seen quite commonly among critically ill patients, so its exact significance remains unclear.
functional fibrinogen measurement
- Determination of the fibrinogen level requires a separate TEG tracing, performed with the addition of a platelet inhibitor (e.g., abciximab).
- In the presence of platelet inhibition, the maximal amplitude (MA) of the curve reflects solely the effect of fibrinogen.
- Incorporation of functional fibrinogen assessment will likely become a standard component of all TEG systems in the near future.
use of TEG to guide blood product transfusion
use of TEG to guide product replacement
- TEG has been validated to guide blood product use in the operating room under a variety of extremely challenging conditions (e.g., liver transplant surgery, cardiothoracic surgery, complex trauma). Outside of the operating room, evidence supporting TEG remains largely centered around patients with cirrhosis.
- Use of TEG to guide product replacement beyond studied contexts seems reasonable:
- (i) Most patients outside of the operating room have less risk of hemorrhage than patients who are actively undergoing surgery.
- (ii) It's illogical to assume that conventional coagulation testing is superior to TEG as a default belief (since, in every context that has been investigated, TEG has been found to be either equivalent or superior compared to conventional coagulation tests).
consensus algorithm of the Society of Cardiovascular Anesthesiologists
- Above is a consensus algorithm on the use of TEG to guide blood product use for management of hemorrhage during cardiothoracic surgery.(31613811) Some points are notable regarding this algorithm:
- (1) The algorithm recognizes that alpha-angle is not a suitable target to drive fibrinogen transfusion (as discussed above). Ideally, the administration of fibrinogen should be based upon the combination of a reduced MA and also a reduction in the functional fibrinogen (FF).
- (2) TEG parameters don't need to be normalized. Rather, only substantially abnormal values may mandate action (e.g., MA <40).
platelet dysfunction in critical illness
Platelet dysfunction has historically been very difficult to test. Consequently, this is a bit of a blind spot for us when evaluating coagulation.
Recently, thromboelastography with platelet mapping has provided clinicians the ability to clinically test specific pathways of platelet activation (more on this below). This was initially conceptualized as a simple test to determine the presence of aspirin or P2Y12 inhibitors (e.g., clopidogrel). However, it has become clear that platelet activation is often inhibited in critically ill patients who haven't been exposed to these medications at all. Thus, there is a lot of complexity here that is only slowly coming into focus. Currently, the role of platelet assessment among critically ill patients remains largely undefined.
thromboelastography with platelet mapping
In standard TEG assays, so much thrombin is generated that platelets will become fully activated, regardless of whether aspirin or P2Y12 inhibitors (e.g., clopidogrel) are present. In order to detect aspirin or P2Y12 inhibitors, modification of the assay is required.
Complete platelet mapping involves the comparison of four curves, as shown above:
- Citrated kaolin-activated TEG (a standard TEG). This evaluates the contributions of platelets plus fibrinogen to clot strength.
- ActF (Activation of Fibrinogen Only). This tracing is generated by the addition of reptilase and factor XIIIa, which solely activate fibrinogen. The amplitude of this curve reflects the contribution of fibrinogen to clot strength.
- AA (Arachidonic Acid) – This tracing is generated by activating fibrinogen (using reptilase and factor XIIIa) and also activating platelets via the arachidonic acid receptor. Normally, this combination should result in fibrinogen plus platelet activation, resulting in an MA which is similar to the citrated kaolin-activated TEG. However, if the arachidonic acid receptors are inhibited by aspirin, then this tracing will be knocked down, pushing it closer to the ActF TEG.
- ADP (Adenosine DiPhosphate) – This tracing is generated by activating fibrinogen (using reptilase and factor XIIIa) and also activating platelets via the ADP receptor. In the presence of P2Y12 inhibitors (e.g., clopidogrel) that block the ADP receptor, this curve will be knocked down below the citrated kaolin-activated TEG.
The risk of bleeding can be assessed in a few different ways:
- % Inhibition measures the percentage that the MA is reduced when platelets are stimulated only via the arachidonic acid or ADP receptor. For example, 95% inhibition with arachadonic acid indicates a strong effect of aspirin on platelets (figure above, left).
- One study of non-cardiac surgery found that, among patients exposed to clopidogrel, below ~35% inhibition with ADP indicated a low risk of perioperative bleeding.(25088505)
- The values of the MA of the AA-TEG and the ADP-TEG may be used to provide a more absolute assessment of clot strength.
Platelet mapping might also provide a clue about fibrinogen function. One study using the TEG6s system found that the maximum amplitude of the ActF tracing correlated with fibrinogen levels (as measured using the Clauss assay; figure below).(33311793) However, this data has yet to be replicated, so it should be interpreted very cautiously.
The precise role of platelet mapping remains to be elucidated. With increasing use of thromboelastography (TEG), the addition of platelet mapping may seem to be a natural extension of this technology.
platelet function analyzer (PFA)
basics of the test
- Whole blood flows through a narrow hole in a membrane coated with collagen and epinephrine, or with collagen and ADP.
- Platelets adhere to the membrane, eventually forming a platelet plug. The time to formation of the platelet plug is the “closure time.”
- Higher closure times suggest impaired platelet function.
- PFA is an integrative test which depends on numerous factors (listed below). Thus, PFA provides a global indicator of overall platelet function. It is not specific for any individual disorder.
- The collagen/epinephrine cartridge tends to be more sensitive than the collagen/ADP cartridge.
factors affecting the PFA
- (1) Platelet count and function (e.g., younger platelets are more active).
- Uremia may cause platelet dysfunction.
- PFA will detect many genetic platelet abnormalities (e.g., Bernard-Soulier syndrome, Glanzmann's thrombasthenia, and von Willebrand disease). However, some mild genetic platelet disorders (e.g., secretion defects) may be missed.
- (2) Plasma levels of von Willebrand factor.
- (3) Hematocrit:
- Higher levels of hematocrit will accelerate plug formation.
- Anemia may prolong the closure time, and thereby could be misconstrued as indicating platelet dysfunction.
- (4) Antiplatelet medications:
- COX inhibitors (e.g., aspirin or NSAIDs) should affect only the collagen/epinephrine cartridge.
- GpIIb/IIIa receptor inhibitors tend to affect both cartridges.
- P2Y12 inhibitors (e.g., clopidogrel) have variable effects. Recently a new cartridge type has been designed for the purpose of detecting P2Y12 inhibition (INNOVANCE PFA P2Y).
possible clinical roles of the PFA
- (1) Screening for von Willebrand disease or other platelet disorders.
- (2) Identification of patients with residual antiplatelet effects (especially from aspirin).
- PFA is a global test of platelet function, so it won't always correlate with aspirin use. For example, patients with high levels of von Willebrand factor may have normal PFA results despite taking aspirin.(27935090)
- Platelet mapping might be superior to evaluate for specific drug effects, since platelet mapping tests the effect of a specific receptor activation (unlike PFA, which evaluates global platelet function).
- (3) Prediction of the hemorrhage risk during surgery:
- PFA may predict the need for platelet transfusion following surgery, especially if closure time is prolonged with both the collagen/epinephrine and collagen/ADP cartridges.(32125177; 30623627) The PFA test has also been recommended to evaluate for antiplatelet medication effect prior to neurosurgery, which seems to be its most common application in the ICU.(26714677)
- If prolonged closure time is detected, pretreatment with DDAVP may reduce the need for perioperative transfusion.(27935090)
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questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- INR and PTT predict clinical bleeding in only very limited contexts (e.g., warfarin or heparin use). Widespread use of FFP to “correct” prolonged INR or PTT is usually nonbeneficial.
- Coagulation tests and blood product administration are overutilized in situations where there is minimal risk of bleeding (e.g., before such minor procedures as central line placement).
- There may be inadequate utilization of clinical context to guide the interpretation of coagulation test interpretation. For example, a fibrinogen level of 125 mg/dL in a patient with DIC who isn't bleeding requires no intervention. Alternatively, in the context of life-threatening hemorrhage, a fibrinogen target >150 mg/dL or even >200 mg/dL could be preferable.
- TEG in cirrhosis (PulmCrit)
- TEG in sepsis-induced DIC (PulmCrit)
- Insanely entertaining lecture by Mark Walsh about TEG (Maryland CC Project)
- Practical-Haemostasis.com – by Dr. David Perry in the UK
- DeLoughery, T. G. (2019). Tests of Hemostasis and Thrombosis. In Hemostasis and Thrombosis (pp. 11–18). Springer International Publishing. https://doi.org/10.1007/978-3-030-19330-0_2
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