Misplaced Pages

#612387

78-464: Mortality associated with severe sepsis remains high at 30-50%. When shock is present, mortality is reported to be even higher at around 50-60%. Approximately 1400 people die from sepsis each day throughout the world. In the U.S. there are approximately 750,000 new sepsis cases each year, with at least 210,000 fatalities and this is reported to be same throughout Europe. As medicine becomes more advanced, with invasive procedures and immunosuppression ,

156-473: A blood vessel . Exposure of blood to the subendothelial space initiates two processes: changes in platelets, and the exposure of subendothelial platelet tissue factor to coagulation factor VII , which ultimately leads to cross-linked fibrin formation. Platelets immediately form a plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously: additional coagulation factors beyond factor VII ( listed below ) respond in

234-412: A carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S , Protein C and Protein Z . In adding the gamma-carboxyl group to glutamate residues on the immature clotting factors, Vitamin K is itself oxidized. Another enzyme, Vitamin K epoxide reductase (VKORC), reduces vitamin K back to its active form. Vitamin K epoxide reductase is pharmacologically important as

312-403: A bleeding disorder. Instead, contact activation system seems to be more involved in inflammation, and innate immunity. Despite this, interference with the pathway may confer protection against thrombosis without a significant bleeding risk. The division of coagulation in two pathways is arbitrary, originating from laboratory tests in which clotting times were measured either after the clotting

390-605: A cascade to form fibrin strands, which strengthen the platelet plug . Coagulation is highly conserved throughout biology. In all mammals , coagulation involves both cellular components (platelets) and proteinaceous components (coagulation or clotting factors). The pathway in humans has been the most extensively researched and is the best understood. Disorders of coagulation can result in problems with hemorrhage , bruising , or thrombosis . There are 13 traditional clotting factors, as named below, and other substances necessary for coagulation: Physiology of blood coagulation

468-478: A circulating LPS-binding protein , and the complex then binds to the CD14 receptor on monocytes , macrophages , and neutrophils . Engagement of CD14 (even at doses as minute as 10 pg/mL) results in intracellular signaling via an associated "Toll-like receptor" protein 4 ( TLR-4 ). This signaling results in the activation of nuclear factor kappaB ( NF-κB ), which leads to transcription of a number of genes that trigger

546-418: A greater risk of mortality than with sepsis alone. Patients with septic shock can be clinically identified by requiring a vasopressor to maintain a mean arterial pressure of 65 mm Hg or greater and having serum lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of hypovolemia . This combination is associated with hospital mortality rates greater than 40%. The primary infection

624-484: A platelet disorder except in severe cases), is the most common hereditary bleeding disorder and is characterized as being inherited autosomal recessive or dominant. In this disease, there is a defect in von Willebrand factor (vWF), which mediates the binding of glycoprotein Ib (GPIb) to collagen. This binding helps mediate the activation of platelets and formation of primary hemostasis. In acute or chronic liver failure , there

702-401: A platelet plug and thereby completing primary hemostasis). The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin formation. These are the contact activation pathway (also known as the intrinsic pathway), and the tissue factor pathway (also known as the extrinsic pathway), which both lead to the same fundamental reactions that produce fibrin. It

780-465: A proinflammatory response. It was the result of significant activation of mononuclear cells and synthesis of effector cytokines. It also results in profound activation of mononuclear cells and the production of potent effector cytokines such as IL-1 , IL-6 , and TNF-α . TLR-mediated activation helps to trigger the innate immune system to efficiently eradicate invading microbes, but the cytokines they produce also act on endothelial cells. There, they have

858-745: A role in septic shock. Septic shock involves a widespread inflammatory response that produces a hypermetabolic effect. This is manifested by increased cellular respiration , protein catabolism , and metabolic acidosis with a compensatory respiratory alkalosis . Most cases of septic shock are caused by gram-positive bacteria , followed by endotoxin-producing gram-negative bacteria , although fungal infections are an increasingly prevalent cause of septic shock. Toxins produced by pathogens cause an immune response; in gram-negative bacteria these are endotoxins , which are bacterial membrane lipopolysaccharides (LPS). In gram-positive bacteria, these are exotoxins or enterotoxins , which may vary depending on

SECTION 10

#1732780052613

936-553: A sequence that starts with Protein C and thrombin binding to a cell surface protein thrombomodulin . Thrombomodulin binds these proteins in such a way that it activates Protein C. The activated form, along with protein S and a phospholipid as cofactors, degrades FVa and FVIIIa. Quantitative or qualitative deficiency of either (protein C or protein S) may lead to thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by having

1014-433: A stage of SIRS (Systemic Inflammatory Response Syndrome), in which sepsis, severe sepsis and multiple organ dysfunction syndrome (MODS) represent different stages of a pathophysiological process. If an organism cannot cope with an infection, it may lead to a systemic response - sepsis, which may further progress to severe sepsis, septic shock, organ failure, and eventually, result in death. Treatment primarily consists of

1092-522: A target of anticoagulant drugs warfarin and related coumarins such as acenocoumarol , phenprocoumon , and dicumarol . These drugs create a deficiency of reduced vitamin K by blocking VKORC, thereby inhibiting maturation of clotting factors. Vitamin K deficiency from other causes (e.g., in malabsorption ) or impaired vitamin K metabolism in disease (e.g., in liver failure ) lead to the formation of PIVKAs (proteins formed in vitamin K absence), which are partially or totally non-gamma carboxylated, affecting

1170-408: A variety of effects, including reduced synthesis of anticoagulation factors such as tissue factor pathway inhibitor and thrombomodulin . The effects of the cytokines may be amplified by TLR-4 engagement on endothelial cells. In response to inflammation, a compensatory reaction of production of anti-inflammatory substances such as IL-4 , IL-10 antagonists, IL-1 receptor, and cortisol occurs. This

1248-410: Is a transglutaminase . The coagulation factors circulate as inactive zymogens . The coagulation cascade is therefore classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin. The main role of the tissue factor (TF) pathway is to generate a "thrombin burst", a process by which thrombin ,

1326-441: Is a potentially fatal medical condition that occurs when sepsis , which is organ injury or damage in response to infection , leads to dangerously low blood pressure and abnormalities in cellular metabolism. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines septic shock as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with

1404-550: Is a selected set of elements of care distilled from evidence-based practice guidelines that, when implemented as a group, have an effect on outcomes beyond implementing the individual elements alone. Each hospital's sepsis protocol may be customized, but it must meet the standards created by the bundle. The first 6-hour SSC Resuscitation Bundle includes: Further management is centered on Early Goal Directed Therapy (EGDT) . Resuscitation Goals are: The 24-hour SSC Management Bundle includes: Septic shock Septic shock

1482-525: Is a subclass of distributive shock , a condition in which abnormal distribution of blood flow in the smallest blood vessels results in inadequate blood supply to the body tissues , resulting in ischemia and organ dysfunction. Septic shock refers specifically to distributive shock due to sepsis as a result of infection. Septic shock may be defined as sepsis-induced low blood pressure that persists despite treatment with intravenous fluids . Low blood pressure reduces tissue perfusion pressure, causing

1560-428: Is also required at other points in the coagulation cascade. Calcium ions play a major role in the regulation of coagulation cascade that is paramount in the maintenance of hemostasis. Other than platelet activation, calcium ions are responsible for complete activation of several coagulation factors, including coagulation Factor XIII. Vitamin K is an essential factor to the hepatic gamma-glutamyl carboxylase that adds

1638-521: Is based on hemostasis , the normal bodily process that stops bleeding. Coagulation is a part of an integrated series of haemostatic reactions, involving plasma, platelet, and vascular components. Hemostasis consists of four main stages: After the fibrin clot is formed, clot retraction occurs and then clot resolution starts, and these two process are together called "tertiary hemostasis". Activated platelets contract their internal actin and myosin fibrils in their cytoskeleton, which leads to shrinkage of

SECTION 20

#1732780052613

1716-540: Is called thrombocytosis , which may lead to formation of thromboembolisms ; however, thrombocytosis may be associated with increased risk of either thrombosis or hemorrhage in patients with myeloproliferative neoplasm . The best-known coagulation factor disorders are the hemophilias . The three main forms are hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency or "Christmas disease") and hemophilia C (factor XI deficiency, mild bleeding tendency). Von Willebrand disease (which behaves more like

1794-417: Is called compensatory anti-inflammatory response syndrome (CARS). Both the inflammatory and anti-inflammatory reactions are responsible for the course of sepsis and are described as MARS (Mixed Antagonist Response Syndrome). The aim of these processes is to keep inflammation at an appropriate level. CARS often leads to suppression of the immune system, which leaves patients vulnerable to secondary infection. It

1872-404: Is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating blood clot formation can be illustrated by the fact that individuals with severe deficiencies of FXII, HMWK, and prekallikrein do not have

1950-435: Is diagnosed if there is low blood pressure (BP) that does not respond to treatment. This means that intravenous fluid administration alone is not enough to maintain a patient's BP. Diagnosis of septic shock is made when systolic blood pressure is less than 90 mm Hg, a mean arterial pressure (MAP) is less than 70 mm Hg, or a systolic BP decrease of 40 mm Hg or more without other causes for low BP. Septic shock

2028-609: Is due to deficiency or abnormal function of von Willebrand factor , and leads to a similar bleeding pattern; its milder forms are relatively common. Decreased platelet numbers (thrombocytopenia) is due to insufficient production (e.g., myelodysplastic syndrome or other bone marrow disorders), destruction by the immune system ( immune thrombocytopenic purpura ), or consumption (e.g., thrombotic thrombocytopenic purpura , hemolytic-uremic syndrome , paroxysmal nocturnal hemoglobinuria , disseminated intravascular coagulation , heparin-induced thrombocytopenia ). An increase in platelet count

2106-426: Is insufficient production of coagulation factors, possibly increasing risk of bleeding during surgery. Thrombosis is the pathological development of blood clots. These clots may break free and become mobile, forming an embolus or grow to such a size that occludes the vessel in which it developed. An embolism is said to occur when the thrombus (blood clot) becomes a mobile embolus and migrates to another part of

2184-537: Is measured by the thrombin clotting time (TCT). Measurement of the exact amount of fibrinogen present in the blood is generally done using the Clauss fibrinogen assay . Many analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot. If a coagulation factor is part of the contact activation or tissue factor pathway, a deficiency of that factor will affect only one of

2262-480: Is most commonly caused by bacteria , but also may be by fungi , viruses or parasites . It may be located in any part of the body, but most commonly in the lungs, brain, urinary tract , skin or abdominal organs . It can cause multiple organ dysfunction syndrome (formerly known as multiple organ failure) and death . Frequently, people with septic shock are cared for in intensive care units . It most commonly affects children, immunocompromised individuals, and

2340-408: Is regulated by plasmin activators and plasmin inhibitors . The coagulation system overlaps with the immune system . Coagulation can physically trap invading microbes in blood clots. Also, some products of the coagulation system can contribute to the innate immune system by their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells . In addition, some of

2418-406: Is released by endothelium and activates platelet G s protein-linked receptors. This, in turn, activates adenylyl cyclase , which synthesizes cAMP. cAMP inhibits platelet activation by decreasing cytosolic levels of calcium and, by doing so, inhibits the release of granules that would lead to activation of additional platelets and the coagulation cascade. Numerous medical tests are used to assess

Surviving Sepsis Campaign - Misplaced Pages Continue

2496-543: Is released from the endothelium and from platelets; vWF forms additional links between the platelets' glycoprotein Ib/IX/V and A1 domain. This localization of platelets to the extracellular matrix promotes collagen interaction with platelet glycoprotein VI . Binding of collagen to glycoprotein VI triggers a signaling cascade that results in activation of platelet integrins. Activated integrins mediate tight binding of platelets to

2574-563: Is tentative evidence that steroids may be useful in improving outcomes. Tentative evidence exists that Polymyxin B-immobilized fiber column hemoperfusion may be beneficial in treatment of septic shock. Trials are ongoing and it is currently being used in Japan and Western Europe. Recombinant activated protein C ( drotrecogin alpha ) in a 2011 Cochrane review was found not to decrease mortality and to increase bleeding, and thus,

2652-491: Is the integration of immune activation into adaptive clot formation. Immunothrombosis is the pathological result of crosstalk between immunity, inflammation, and coagulation. Mediators of this process include damage-associated molecular patterns and pathogen-associated molecular patterns , which are recognized by toll-like receptors , triggering procoagulant and proinflammatory responses such as formation of neutrophil extracellular traps . Various substances are required for

2730-457: Is the preferred vasopressor, while epinephrine may be added to norepinephrine when needed. Low-dose vasopressin also may be used as an addition to norepinephrine, but is not recommended as a first-line treatment. Dopamine may cause rapid heart rate and arrhythmias , and is only recommended in combination with norepinephrine in those with slow heart rate and low risk of arrhythmia. In the initial treatment of low blood pressure in septic shock,

2808-419: Is the process by which blood changes from a liquid to a gel , forming a blood clot . It results in hemostasis , the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation , adhesion and aggregation of platelets , as well as deposition and maturation of fibrin . Coagulation begins almost instantly after an injury to the endothelium that lines

2886-441: Is thought to be via the inhibition of the nitric oxide - cyclic guanosine monophosphate pathway. This pathway is excessively activated in septic shock. Methylene blue has been found to work in cases resistant to the usual agents. This effect was first reported in the early 1990s. While there is tentative evidence for β-Blocker therapy to help control heart rate , evidence is not significant enough for its routine use. There

2964-400: The tissue hypoxia that is characteristic of shock. Cytokines released in a large scale inflammatory response result in massive vasodilation , increased capillary permeability , decreased systemic vascular resistance , and low blood pressure. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction occur. Septic shock may be regarded as

3042-647: The "Leiden" variant of Factor V or high levels of FVIII, also may lead to a thrombotic tendency. Antithrombin is a serine protease inhibitor ( serpin ) that degrades the serine proteases: thrombin, FIXa, FXa, FXIa, and FXIIa. It is constantly active, but its adhesion to these factors is increased by the presence of heparan sulfate (a glycosaminoglycan ) or the administration of heparins (different heparinoids increase affinity to FXa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g., in proteinuria ) leads to thrombophilia. Tissue factor pathway inhibitor (TFPI) limits

3120-469: The action of tissue factor (TF). It also inhibits excessive TF-mediated activation of FVII and FX. Plasmin is generated by proteolytic cleavage of plasminogen, a plasma protein synthesized in the liver. This cleavage is catalyzed by tissue plasminogen activator (t-PA), which is synthesized and secreted by endothelium. Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation. Prostacyclin (PGI 2 )

3198-399: The administration of broad-spectrum antibiotics within the first hour following recognition of septic shock. Prompt antimicrobial therapy is important, as risk of dying increases by approximately 10% for every hour of delay in receiving antibiotics. Time constraints do not allow the culture, identification, and testing for antibiotic sensitivity of the specific microorganism responsible for

Surviving Sepsis Campaign - Misplaced Pages Continue

3276-621: The body, interfering with blood circulation and hence impairing organ function downstream of the occlusion. This causes ischemia and often leads to ischemic necrosis of tissue. Most cases of venous thrombosis are due to acquired states (older age, surgery, cancer, immobility). Unprovoked venous thrombosis may be related to inherited thrombophilias (e.g., factor V Leiden , antithrombin deficiency, and various other genetic deficiencies or variants), particularly in younger patients with family history of thrombosis; however, thrombotic events are more likely when acquired risk factors are superimposed on

3354-410: The classic extrinsic pathway and contributes to about 5% of thrombin production. The amplified production of thrombin occurs via the classic intrinsic pathway in the propagation phase; about 95% of thrombin generated will be during this second phase. Eventually, blood clots are reorganized and resorbed by a process termed fibrinolysis . The main enzyme responsible for this process is plasmin , which

3432-404: The clot volume. Plasminogen activators , such as tissue plasminogen activator (t-PA), activate plasminogen into plasmin, which promotes lysis of the fibrin clot; this restores the flow of blood in the damaged/obstructed blood vessels. When there is an injury to a blood vessel, the endothelial cells can release various vasoconstrictor substances, such as endothelin and thromboxane, to induce

3510-465: The coagulation factors' ability to bind to phospholipid. Several mechanisms keep platelet activation and the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis: Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C (APC). Protein C is activated in

3588-471: The constriction of the smooth muscles in the vessel wall. This helps reduce blood flow to the site of injury and limits bleeding. When the endothelium is damaged, the normally isolated underlying collagen is exposed to circulating platelets, which bind directly to collagen with collagen-specific glycoprotein Ia/IIa surface receptors. This adhesion is strengthened further by von Willebrand factor (vWF), which

3666-481: The earlier definitions of sepsis updated in 2001, sepsis is a constellation of symptoms secondary to an infection that manifests as disruptions in heart rate, respiratory rate, temperature, and white blood cell count. If sepsis worsens to the point of end-organ dysfunction (kidney failure, liver dysfunction, altered mental status, or heart damage), then the condition is called severe sepsis. In septic shock, events within tissue capillaries induce distributive shock in which

3744-559: The elderly, as their immune systems cannot deal with infection as effectively as those of healthy adults. The mortality rate from septic shock is approximately 25–50%. Septic shock is a result of a systemic response to infection or multiple infectious causes. The precipitating infections that may lead to septic shock if severe enough include but are not limited to appendicitis , pneumonia , bacteremia , diverticulitis , pyelonephritis , meningitis , pancreatitis , necrotizing fasciitis , MRSA and mesenteric ischemia . According to

3822-439: The emergence of MRSA and the increased use of arterial and venous catheters, gram-positive bacteria are implicated approximately as commonly as bacilli . In rough order of increasing severity these are, bacteremia or fungemia; sepsis, severe sepsis or sepsis syndrome; septic shock, refractory septic shock, multiple organ dysfunction syndrome, and death. 35% of septic shock cases derive from urinary tract infections , 15% from

3900-478: The extracellular matrix. This process adheres platelets to the site of injury. Activated platelets release the contents of stored granules into the blood plasma. The granules include ADP , serotonin , platelet-activating factor (PAF), vWF , platelet factor 4 , and thromboxane A 2 (TXA 2 ), which, in turn, activate additional platelets. The granules' contents activate a G q -linked protein receptor cascade, resulting in increased calcium concentration in

3978-487: The fibrin network. The coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex until it is down-regulated by the anticoagulant pathways. A newer model of coagulation mechanism explains the intricate combination of cellular and biochemical events that occur during the coagulation process in vivo . Along with the procoagulant and anticoagulant plasma proteins, normal physiologic coagulation requires

SECTION 50

#1732780052613

4056-423: The following: Because lowered blood pressure in septic shock contributes to poor perfusion, fluid resuscitation is an initial treatment to increase blood volume. Patients demonstrating sepsis-induced hypoperfusion should be initially resuscitated with at least 30 ml/kg of intravenous crystalloid within the first three hours. Crystalloids such as normal saline and lactated Ringer's solution are recommended as

4134-580: The function of the coagulation system: The contact activation (intrinsic) pathway is initiated by activation of the contact activation system , and can be measured by the activated partial thromboplastin time (aPTT) test. The tissue factor (extrinsic) pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test. PT results are often reported as ratio ( INR value) to monitor dosing of oral anticoagulants such as warfarin . The quantitative and qualitative screening of fibrinogen

4212-540: The goal of vasopressor treatment is a mean arterial pressure (MAP) of 65 mm Hg. In 2017, the FDA approved angiotensin II injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock. Methylene blue has been found to be useful for this condition. Although use of methylene blue has mostly been in adults it has also been shown to work in children. Its mechanism of action

4290-464: The incidence of sepsis is likely to increase even more. Sepsis is one of the complications of Coronavirus disease 2019 . In 2020, the campaign produced Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 . This is done using a six-pronged approach: Using bundles in health care simplifies the complex processes of the care of patients with severe sepsis. A bundle

4368-414: The infection. Therefore, combination antimicrobial therapy, which covers a wide range of potential causative organisms, is tied to better outcomes. Antibiotics should be continued for 7–10 days in most patients, though treatment duration may be shorter or longer depending on clinical response. Among the choices for vasopressors , norepinephrine is superior to dopamine in septic shock. Norepinephrine

4446-410: The inherited state. The use of adsorbent chemicals, such as zeolites , and other hemostatic agents are also used for sealing severe injuries quickly (such as in traumatic bleeding secondary to gunshot wounds). Thrombin and fibrin glue are used surgically to treat bleeding and to thrombose aneurysms. Hemostatic Powder Spray TC-325 is used to treated gastrointestinal bleeding. Desmopressin

4524-458: The initial fluid of choice, while the use of colloid solutions such as hydroxyethyl starch have not shown any advantage or decrease in mortality. When large quantities of fluids are given, administering albumin has shown some benefit. However, too high of a rate of fluid infusion can be more risky; the particular type of fluid's flow rate must be closely monitored, along with the patient's condition and vital signs. Treatment guidelines call for

4602-401: The initiation of the platelet plug, which in turn promotes more platelet activation. Thrombin functions not only to convert fibrinogen to fibrin, it also activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin ). By activating Factor XIII, covalent bonds are formed that crosslink the fibrin polymers that form from activated monomers. This stabilizes

4680-468: The lung, and activation of the coagulation system culminating in disseminated intravascular coagulation (DIC). The hypoperfusion from the combined effects of widespread vasodilation, myocardial pump failure, and DIC causes multiorgan system failure that affects the liver, kidneys, and central nervous system, among other organ systems. Recently, severe damage to liver ultrastructure has been noticed from treatment with cell-free toxins of Salmonella . Unless

4758-728: The most frequent cause of death in intensive care units. There has been an increase in the rate of septic shock deaths in recent decades, which is attributed to an increase in invasive medical devices and procedures, increases in immunocompromised patients, and an overall increase in elderly patients. Tertiary care centers (such as hospice care facilities) have 2-4 times the rate of bacteremia than primary care centers, 75% of which are hospital-acquired infections . The process of infection by bacteria or fungi may result in systemic signs and symptoms that are variously described. Approximately 70% of septic shock cases were once traceable to gram-negative bacteria that produce endotoxins , however, with

SECTION 60

#1732780052613

4836-451: The most important constituent of the coagulation cascade in terms of its feedback activation roles, is released very rapidly. FVIIa circulates in a higher amount than any other activated coagulation factor. The process includes the following steps: The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein , and FXII (Hageman factor) . Prekallikrein

4914-474: The nature of the defect. Platelet disorders are either congenital or acquired. Examples of congenital platelet disorders are Glanzmann's thrombasthenia , Bernard–Soulier syndrome (abnormal glycoprotein Ib-IX-V complex ), gray platelet syndrome (deficient alpha granules ), and delta storage pool deficiency (deficient dense granules ). Most are rare. They predispose to hemorrhage. Von Willebrand disease

4992-438: The next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals , with a lowercase a appended to indicate an active form. The coagulation factors are generally enzymes called serine proteases , which act by cleaving downstream proteins. The exceptions are tissue factor, FV, FVIII, FXIII. Tissue factor, FV and FVIII are glycoproteins, and Factor XIII

5070-976: The other hand, such LPS would not be able to induce septic shock in susceptible patients, rendering septic complications more manageable. Yet, defining and understanding how even the smallest structural differences between the very similar LPS species may affect the activation of the immune response may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes. According to current guidelines, requirements for diagnosis with sepsis are "the presence (probable or documented) of infection together with systemic manifestations of infection". These manifestations may include: Documented evidence of infection may include positive blood culture , signs of pneumonia on chest x-ray, or other radiologic or laboratory evidence of infection. Signs of end-organ dysfunction are present in septic shock, including kidney failure , liver dysfunction, changes in mental status, or elevated serum lactate . Septic shock

5148-477: The platelets' cytosol. The calcium activates protein kinase C , which, in turn, activates phospholipase A 2 (PLA 2 ). PLA 2 then modifies the integrin membrane glycoprotein IIb/IIIa , increasing its affinity to bind fibrinogen . The activated platelets change shape from spherical to stellate, and the fibrinogen cross-links with glycoprotein IIb/IIIa aid in aggregation of adjacent platelets, forming

5226-427: The presence of two cell types for formation of coagulation complexes: cells that express tissue factor (usually extravascular) and platelets. The coagulation process occurs in two phases. First is the initiation phase, which occurs in tissue-factor-expressing cells. This is followed by the propagation phase, which occurs on activated platelets . The initiation phase, mediated by the tissue factor exposure, proceeds via

5304-470: The products of the coagulation system are directly antimicrobial . For example, beta-lysine , an amino acid produced by platelets during coagulation, can cause lysis of many Gram-positive bacteria by acting as a cationic detergent. Many acute-phase proteins of inflammation are involved in the coagulation system. In addition, pathogenic bacteria may secrete agents that alter the coagulation system, e.g. coagulase and streptokinase . Immunohemostasis

5382-443: The proper functioning of the coagulation cascade: Calcium and phospholipids (constituents of platelet membrane) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on Factor Xa and Factor IXa to the phospholipid surfaces expressed by platelets, as well as procoagulant microparticles or microvesicles shed from them. Calcium

5460-445: The recovery of blood pressure is not achieved upon the administration of additional intravenous fluids, and requires a vasoconstrictive agent such as noradrenaline and/or vasopressin. The pathophysiology of septic shock is not entirely understood, but it is known that a key role in the development of severe sepsis is played by an immune and coagulation response to an infection. Both pro-inflammatory and anti-inflammatory responses play

5538-444: The respiratory tract, 15% from skin catheters (such as IVs ), and more than 30% of all cases are idiopathic in origin. The mortality rate from sepsis, especially if it is not treated rapidly with the needed medications in a hospital, is approximately 40% in adults and 25% in children. It is significantly greater when sepsis is left untreated for more than seven days. Coagulation Coagulation , also known as clotting ,

5616-593: The species of bacteria. These are divided into three types. Type I, cell surface-active toxins, disrupt cells without entering, and include superantigens and heat-stable enterotoxins . Type II, membrane-damaging toxins, destroy cell membranes in order to enter and include hemolysins and phospholipases . Type III, intracellular toxins or A/B toxins interfere with internal cell function and include shiga toxin , cholera toxin , and anthrax lethal toxin . (note that Shigella and Vibrio cholerae are Gram negative organisms). In gram-negative sepsis, free LPS attaches to

5694-637: The tests: Thus hemophilia A , a deficiency of factor VIII, which is part of the contact activation pathway, results in an abnormally prolonged aPTT test but a normal PT test. Deficiencies of common pathway factors prothrombin, fibrinogen, FX, and FV will prolong both aPTT and PT. If an abnormal PT or aPTT is present, additional testing will occur to determine which (if any) factor is present as aberrant concentrations. Deficiencies of fibrinogen (quantitative or qualitative) will prolong PT, aPTT, thrombin time, and reptilase time . Coagulation defects may cause hemorrhage or thrombosis, and occasionally both, depending on

5772-458: The underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies. The ability of TLR4 to respond to a distinct LPS species are clinically important. Pathogenic bacteria may employ LPS with low biological activity to evade proper recognition by the TLR4 / MD-2 system, dampening the host immune response and increasing the risk of bacterial dissemination. On

5850-401: Was initiated by glass, the intrinsic pathway; or clotting was initiated by thromboplastin (a mix of tissue factor and phospholipids), the extrinsic pathway. Further, the final common pathway scheme implies that prothrombin is converted to thrombin only when acted upon by the intrinsic or extrinsic pathways, which is an oversimplification. In fact, thrombin is generated by activated platelets at

5928-524: Was not recommended for use. Drotrecogin alfa (Xigris), was withdrawn from the market in October 2011. Sepsis has a worldwide incidence of more than 20 million cases a year, with mortality due to septic shock reaching up to 50 percent even in industrialized countries. According to the U.S. Centers for Disease Control , septic shock is the thirteenth leading cause of death in the United States and

6006-606: Was once thought that SIRS or CARS could predominate in a septic individual, and it was proposed that CARS follows SIRS in a two-wave process. It is now believed that the systemic inflammatory response and the compensatory anti-inflammatory response occur simultaneously. At high levels of LPS, the syndrome of septic shock supervenes; the same cytokine and secondary mediators, now at high levels, result in systemic vasodilation (hypotension), diminished myocardial contractility, widespread endothelial injury, activation causing systemic leukocyte adhesion and diffuse alveolar capillary damage in

6084-428: Was previously thought that the two pathways of coagulation cascade were of equal importance, but it is now known that the primary pathway for the initiation of blood coagulation is the tissue factor (extrinsic) pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze

#612387