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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica, Inc.

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INTRODUCTION:

Sepsis is complex and occurs in 2.5/1000 individuals with an increase seen of 8.7% over the last 20 years due to an aging population. It is a leading cause of mortality with 19 million cases resulting in 5 million deaths globally.¹

There is a large link between inflammation and coagulation, so coagulopathy is common in sepsis. The hemostatic balance in sepsis is disrupted. Coagulation is activated, while the anticoagulant mechanisms of fibrinolysis and anticoagulation factors are suppressed².

The definition of sepsis is life-threatening organ dysfunction due to an unregulated response to infection. Inflammation and coagulation both contribute to the pathogenesis of organ dysfunction. Thrombo-inflammation is due to activated platelets, leukocytes as well as endothelial cell damage results in the formation of microthrombi in the capillaries.³

One of the reasons to detect sepsis induced coagulation (SIC) is to mitigate the risk of overt DIC. Non-overt DIC is an initially compensated derangement of the hemostatic system which then becomes overt DCI. This is when the Coagulation system is decompensated.²

SCORING:

SIC needs to be differentiated from HIT, cirrhosis and thrombotic microangiopathy. SIC is not homogenous and can vary based on demographics, comorbidities and failed organs. In 2017 a scoring system was developed to identify sepsis induced coagulopathy. In 2019 the ISTH adopted the scoring system, and it was used globally. The Sequential Organ Failure Assessment (SOFA) score was developed.⁴

The score calculated by the sum of respiratory, hepatic, cardiovascular, and renal dysfunction scores: 1 point if 1, 2 points if ≥ 2. The patients are diagnosed with SIC when the total score is 4 or more. When 28-day mortality was reviewed the PT and SOFA scores were found to be independent predictors for mortality. The diagnosis of SIC is based on decreased platelet count: 1 point if 100–150 × 10⁹/L, 2 points if < 100 × 10⁹/L; prothrombin time/international normalized ratio (PT-INR): 1 point if 1.2–1.4, 2 points if > 1.4.³

MECHANISM:

The process of cytokine induces coagulation amplification results in a prothrombotic state from activation of the extrinsic pathway. It also results in the suppression of anticoagulation pathway and fibrinolysis resulting in DIC and hypercoagulability. Bacterial toxins are stimuli for activation of the coagulation cascade and DIC. In the early stages of sepsis AT, PC and TFPI count acts the process as these become consumed and as a result a decrease in activity occurs, in particular AT. This then contributes to a hyper-coagulable state. Fibrinolysis depends on the balance of t-PA and PAI-1. TPA works though fibrin degradation by plasmin, while PAI-1 inhibits fibrinolysis. This balance is disrupted further leading to a hypercoagulable state.²

In DIC patients present with decreased platelets, increased PT and FDPs and a decreased fibrinogen, however this occurs in the later stages of DIC. The goal is to identify patients earlier using other assays such as measuring anticoagulation proteins, nuclear material levels and viscoelastic testing. These have shown to have good sensitivity and specificity leading to early treatment.²

TESTING:

Decreased platelets are an independent predictor of poor outcomes in sepsis. Sepsis activates platelets which aggregate with WBC. This causes increased sequestration in the spleen.²

Fibrin related markers such as FDP's and D-dimers are elevated. FDP were found in 99% of patients but are non-specific. D-dimers result from proteolysis of cross-linked fibrin and are more specific. D-dimers indicate that thrombin prompted the conversion of fibrinogen to fibrin which is cross linked by FXIII and degraded by plasmin.²

Fibrinogen is an acute phase reactant and may look to be in the normal range in DIC until later in the process when it is consumed and is decreased.²

Viscoelastic testing such as TEG and ROTEM evaluate the entire coagulation process from initiation, clot formation to clot dissolution. As a result, this can detect DIC earlier. ROTEM can detect hypo & hyper coagulation risk. A study showed patients with overt DIC had a hypo profile while those without overt DIC presented with a hyper profile. All patients had a normal coagulation profile.² Viscoelastic testing showed that maximum clot firmness (MCF) was increased in sepsis and severe sepsis when compared to healthy controls. While normal MCF and a prolonged clot development was observed in septic shock. Fibrinolytic activity was positively correlated with 28 day mortality.⁵

Thrombin antithrombin (TAT) is a marker of thrombin generation and can be used to identify patients with DIC. Higher levels of TT were reported in DIC patients and levels correlated with the risk of mortality²

PAI-1 can be used with other biomarkers as increased levels were associated with increased mortality risks.²

An observational study of 444 patients of suspected DIC and 137 healthy controls showed that a combination of four biomarkers provided more reliable results than when one biomarker was used. TAT was used for thrombin generation, t-pa inhibitor complex looks at microthrombus formation, alpha 2 antiplasmin complex indicated plasmin generation and soluble thrombomodulin (sTM). All are predictors of poor outcomes.⁶

Thrombomodulin plays an important role in coagulation. sTM is the result of proteolytic degradation of endothelial bound TM which is released from the endothelial surface making it a marker of endothelial damage.⁶ In a study of 372 patients with sepsis in which 210 were classified as severe and 98 patients had septic shock, sTM was a valuable biomarker in emergency room sepsis. This resulted in a poor 60 day prognosis and development of septic shock as well as sepsis induced DIC.⁷

ETP showed conflicting results, but a study recently showed a correlation between increased infection severity and decrease ability of thrombin generation and could aid in the prediction of multiorgan dysfunction and poor outcomes. PF 1.2 can also be used as a marker. ADAMTS-13 which is a vWF cleaving protease which decreased prothrombotic properties. A deficiency leads to ultra large vWF and thrombotic microangiopathy which is associated with severity of sepsis and poor prognosis.²

C-type lectin like receptor 2 (CLEC-2) is a platelet activator receptor found on the surface of platelets. In a study of 70 septic patients, it was found that the C2PAC index was higher in the SIC group versus non-SIC patients (2.6 +/- 1.7 vs 1.2 +/-0.5). This risk may indicate a progression to DIC.⁶

Neutrophil extracellular traps (NETS) have demonstrated a link between inflammation and thrombosis. NETS are a product of a response to microbial infection. Along with platelets, RBC and fibrin, NETS promote the formation of thrombi. In 82 patients with sepsis, increased NETS were associated with sepsis induced DIC.⁶

Angiopoietin-2 (ANG-2) is stored in Weibel-Palade bodies with vWF. ANG-2 is a secreted protein found in endothelial cells. Its release may precede profound endothelial injury.6 In a study of 105 patients, ANG-2 levels increased in proportion to the severity of sepsis as well as platelet count, arterial pressure, procalcitonin, lactate and SOFA scores. This marker can be used to stratify sepsis as being overt or non-overt DIC. It may also be a predictive biomarker for mortality.⁸

CONCLUSION:

SIC is a very serious condition that requires a quick diagnosis so treatment can be instituted and minimize organ damage as well as mortality. Unfortunately, by the time routine coagulation testing is impacted, DIC has progressed. Being able to assess patients using new tests can aid in the diagnosis and initiation of treatment. Understanding what test may be beneficial to increase sensitivity and specificity will optimize patient diagnosis.

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REFERENCES:

1. Giustozzi M., Ehrlinder H., Bongiovanni D., Borovac J.A., Guerreiro R.A., Gąsecka A., Papakonstantinou P.E., Parker W.A. Coagulopathy and sepsis: Pathophysiology, clinical manifestations and treatment. Blood Rev. 2021.
2. Giustozzi M., Ehrlinder H., Bongiovanni D., Borovac J.A., Guerreiro R.A., Gąsecka A., Papakonstantinou P.E., Parker W.A. Coagulopathy and sepsis: Pathophysiology, clinical manifestations and treatment. Blood Rev. 2021.
3. Iba T, Helms J, Levy JH. Sepsis-induced coagulopathy (SIC) in the management of sepsis. Ann Intensive Care. 2024 Sep 20;14(1):148
4. Iba T, Levi M, Thachil J, Helms J, Scarlatescu E, Levy JH. Communication from the scientific and standardization committee of the international society on thrombosis and haemostasis on sepsis-induced coagulopathy in the management of sepsis. J Thromb Haemost. 2023;21(1):145–53
5. Sharma P., Saxena R. A Novel Thromboelastographic Score to Identify Overt Disseminated Intravascular Coagulation Resulting in a Hypocoagulable State. Am. J. Clin. Pathol. 2010;134:97–102.
6. Sharma P., Saxena R. A Novel Thromboelastographic Score to Identify Overt Disseminated Intravascular Coagulation Resulting in a Hypocoagulable State. Am. J. Clin. Pathol. 2010;134:97–102.
7. Yin Q, Liu B, Chen Y, et al. The role of soluble thrombomodulin in the risk stratification and prognosis evaluation of septic patients in the emergency department. Thromb Res. 2013;132(4):471-476
8. Statz S, Sabal G, Walborn A, et al. Angiopoietin 2 levels in the risk stratification and mortality outcome prediction of sepsis-associated coagulopathy. Clin Appl Thromb Hemost. 2018;24(8):1223-1233

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