The Daily Dose • Monday, May 20
The Treatment of Sepsis: Simple Interventions Could Save Lives
By Amanda Decimo, MSN, MPH, CRNA, from the IARS, AUA and SOCCA 2019 Annual Meetings*
The SOCCA panel, Sepsis-Induced Coagulopathy: Mechanisms and Management, presented by Jean-Francois Pittet, MD, Brittney Williams, MD, and Jecko Thachil, MD, on Sunday, May 19, focused on sepsis-induced coagulopathy (SIC), a unique clinical syndrome characterized by persistent coagulation activation and fibrinolytic suppression. While SIC management is complex and elusive, this session offered guidance for earlier diagnosis and improved care of these complex patients.
The coagulation system is a well-orchestrated process involving all blood cells, and it contains bleeding at the site of injury. What is often overlooked is that it also serves as an important anti-septic system. Inflammation and coagulation are linked to the same evolutionary processes. The changes that occur in the coagulation system as a result of sepsis are intended to sequester infectious pathogens.
Our body’s hemostatic balance is maintained like a weighted pendulum – clotting factors and platelets on one side and anticoagulants and von Willebrand factor (vWF) on the other. In sepsis, the weight shifts towards clotting, as the body attempts to prevent infection from spreading by forming a blood clot.
The vascular endothelium is a single layer of cells that lines all blood vessels in the body. It creates the dialogue between blood and the underlying tissue. The endothelial glycocalyx is a network of glycoproteins and proteoglycans (including heparin-like substances) that covers this endothelium. Endothelial glycocalyx maintains microvascular tone, oncotic gradients, leukocyte migration, and prevents intravascular thrombosis.
During sepsis, damage to the vascular endothelium and it’s glycocalyx layer from catecholamine release results in multiple maladaptive responses:
- Increased microvascular permeability
- Inhibition of ADAMTS 13 and massive release of vWF antigen
- Intravascular immunothrombosis
- Systemic autoheparinization (heparin sulfate release)
- Systemic anticoagulation (active protein C release)
- Hyperfibrinolysis (endogenous tissue plasminogen activator (tPA) release) or fibrinolysis shutdown
Heparin sulfate cleavage also increases endothelial permeability. An interesting article by Zhang et al., entitled, “Circulating Heparin Oligosaccharides Rapidly Target the Hippocampus in Sepsis, Potentially Impacting Cognitive Functions,” demonstrates that cognitive function gives us another indication that heparin sulfate plays a significant role in sepsis.
Sepsis is defined as life-threatening organ dysfunction secondary to a dysregulated host response leading to exaggerated inflammation (definition from Sepsis-3 consensus). The inflammation and coagulation hallmark responses that occur ultimately result in impaired tissue perfusion, organ dysfunction, and mortality.
Dr. Thachil, Manchester Royal Infirmary Haematology, described sepsis-induced coagulopathy (SIC) from the eyes of an experienced hematologist. He explained disseminated intravascular coagulation (DIC) may actually be an acronym for Death Is Coming. By the time the diagnosis of DIC is made, it may be too late.
Thrombin is the most valuable player of the coagulation system. It helps form an appropriate blood clot at the site of injury by balancing all the pathways (coagulation, fibrinolytic, and platelet). In DIC, thrombin generation is uncontrolled.
A platelet is an antibacterial, antiparasitic, and antiviral cell. In this way, platelet count changes during infections and thrombocytopenia occurs in sepsis. A falling platelet count is more important than an absolute value. Are septic patients with thrombocytopenia going to bleed? No. The thrombocytopenia opens up the microvasculature and causes petechiae, brain edema, acute lung injury, and peripheral edema. The platelet aggregation also leads to microthrombi that can cause organ failure. Blocking platelet aggregation with aspirin or clopidogrel is an innovative approach in SIC management that many physicians are afraid to try with low platelet counts.
Fibrinogen is the most important clotting factor in SIC. It is the most abundant factor and key component of the thrombus. Fibrinogen may play a protective role in sepsis, and low levels found on laboratory monitoring may be an indicator of poor prognosis.
There is a need for new diagnostic markers for DIC. Prothrombin time and partial thromboplastin time will only be prolonged if multiple coagulation factors are low. This is not very common in SIC and the values will not be useful. Dr. Thachil’s suggestion is to try to catch the platelet count and fibrinogen when they are going up. This is when the coagulation cascade is being activated, and the body is trying to fight the infection. Waiting until later will be too late. Consider the trends.
Dr. Thatchil’s treatment strategy centers around blocking dysregulated thrombin. In the absence of bleeding, he recommends considering low molecular weight heparin (LMWH) for its antithrombotic and anti-inflammatory properties. Blood products are not usually required, and no data exist to support their use. Recombinant thrombomodulin is a promising new target under investigation. The best treatment for septic DIC is preventing and controlling infection and its associated inflammation. Consider the pathophysiology, detect it earlier, and use simple interventions.
*Coverage from the SOCCA Panel: Sepsis-Induced Coagulopathy: Mechanisms and Management at the IARS 2019 Annual Meeting