Chapter 4: Hemodynamic Disorders, Thromboembolic Disease, and Shock Flashcards
Reduced plasma osmotic pressure is caused by what?
- Liver disease; protein malnutrition = decreased synthesis of albumin
- Nephrotic syndrome (kidney) = increased loss of albumin
Increased hydrostatic pressure is caused by what?
Most often due to impaired venous return, may be localized (i.e., DVT) or systemic (i.e., CHF)
CHF may lead to renal hypoperfusion, which results in the activation of?
Affect on hydrostatic pressure and plasma colloid osmotic pressure?
- Activation of the RAAS system (reabsorbs sodium and water follows)
- Causes increased hydrostatic pressure due to intravascular volume expansion
- Decreased vascular colloid osmotic pressure due to dilution
What can cause edema via lymphatic obstruction?
Surgical removal and/or radiation of what can lead to severe edema of the UE?
- Trauma, fibrosis, invasive tumors, and microbes
- Decreased ability of lymph system to take up the fluid results in lymphedema
- -* Surgical removal and/or radiation of the breast and associated axillary LN’s in breast cancer pt’s.
What effect does the parasitic filariases have on the lymphatics?
Results in?
- Obstructive fibrosis of the lymph channels and nodes
- Edema of the external genitalia and lower limbs that can be very extreme and called elephantiasis
How do you describe Transudative effusion?
Protein poor, serous, straw-colored; non-inflammatory
Characteristics of exudative effusion?
Protein rich, opaque (cloudy), increased WBCs; inflammatory
Subcutaneous edema is important because it may signify what?
Cardiac or renal disease
Edema resulting from renal dysfunction initially appears where?
What is a characteristic sign of severe renal disease?
- Parts of the body containing loose CT, such as the eyelids.
- Periorbital edema is a characteristic finding of severe renal disease
Pulmonary edema is most commonly secondary to?
CHF (left ventricular failure)
Ascites is often seen in context of _________ disease?
Severe liver disease
Increased blood volume in tissue, either locally or systemically is called what?
Result of what?
- Hyperemia
- Active process w/ arteriolar dilation = increased arterial blood delivery to a given location (i.e., sites of inflammation or in skeletal muscle during exercise)
- Often physiologic
Congestion is the result of what?
Causes what?
Chronic cases lead to what?
- Passive process that = decreased blood outflow; systemic (i.e., cardiac failure) or localized obstruction
- Increases hydrostatic pressure, which may lead to edema
- Chronic cases may lead to hypoxia and ischemia
In chronic pulmonary congestion, which is often caused by CHF, the septa are thick and fibrotic, and the alveoli contain what telltale (diagnostic) sign?
Hemosiderin-laden macrophages, called heart failure cells
Morphologically, what appearance do congested tissues take on?
- Dusky, reddish-blue color (cyanosis) due to red cell stasis and deoxygenated hemoglobin
- “Blue and bloated’‘
What is the morphology seen with chronic passive hepatic congestion?
- Nutmeg liver = centrilobular regions are grossly red-brown and slightly depressed
- Microscopically there is centrilobular hemorrhage and hemosiderin-laden macrophages
What is the 1st thing that happens in Hemostasis at the site of vascular injury?
What mediates this process?
- Arteriolar vasoconstriction (AKA vasospasm)
- Neurogenic reflexes mechanisms and augmented by factors such as endothelin released from the endothelium
Where do platelets come from?
Megakaryocytes from bone marrow
What is the 2nd event at the site of injury during hemostasis?
Mediated by?
- Exposure of subendothelial von Willebrand factor (vWF) and collagen promote platelet adherance and activation
- Platelets shape change to flate plate w/ spiky protrusions to increase S.A.
- Platelets also release granules which recruit more platelets to the area to form a primary hemostatic plug
What do alpha-granules of platelets contain?
Which adhesion molecule on their membranes?
Fibrinogen
Factor V
vWF
Wound healing: fibronectin, platelet factor 4, PDGF
On their membranes: P-selectin
What do delta-granules of platelets contain?
Ca2+
ADP
ATP
Serotonin
Epinephrine
Platelet adhesion occurs via what interaction?
vWF binds to platelet surface receptor GpIb
As the platelet becomes activated and takes on a new shape, resembling a spiky sea urchin, what alterations to the platelet occur?
- Glycoprotein IIb/IIIa increases its affinity for fibrinogen
- Translocation of negatively charged phospholipids (particularly phosphatidylserine) to the platelet surface
Activated platelets produce what potent inducer of platelet aggregation?
What inhibits this?
- Thromboxane A2 (TxA2)
- Cyclooxygenase required for synthesis (inhibted by aspirin)
Platelets aggregate and link through what interaction?
Fibrinogen - GpIIb/IIIa
During secondary hemostasis what occurs to consolidate the initial platelet plug?
What are the mediators?
- Tissue factor is exposed at the site of injury, which can then bind and activate factor VII
- Results in the generation of thrombin, which cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork and also recruits and activates more platelets
- Ultimately this process stabilizes the clot
What additional role does thrombin serve on endothelium?
Acts on normal endothelium to limit clot size
Which counterregulatory molecules limit the clotting to the site of injury?
- tPA
- Thrombomodulin
Thrombin is a potent inducer of platelet activation and aggregation through its ability to activate platelets through what kind of receptor?
What is the name of the receptor?
- GPCR
- Protease-activated receptor (PAR)
Assembly of reaction complexes for the clotting cascade depends on ____?
Where does this molecule bind and on what factors?
- Dependent on Ca2+, which binds γ-carboxylated glutamic acid residues present on:
- Factors X, IX, VII, and II (prothrombin)
Glanzmann thrombasthenia is a inherited genetic deficiency of?
Defect of?
GpIIb-IIIa
Defect of primary hemostasis, platelets are impaired
Enzymatic reactions that produce γ-carboxylated glutamic acid residues use what as a cofactor?
Are antagonized by what drug?
- Vitamin K as a cofactor
- Antagonized by coumadin
What is the the most potent activator of factor IX and of factor X?
- Factor (7a) VIIa/TF complex activates Factor IX
- Factor (9a) IXa/Factor (8a) VIIIa complex activates Factor X
Thrombin feeds back and amplifies the coagulation cascade by activating what which factors?
XI, VIII, and V
(eleven, eight, five)
What does PT measure; which factors?
What must you add?
- Extrinsic pathway; factors VII, X, V, II, fibrinogen
- Add TF, phospholipids and Ca2+
(10, 7, 5, 2, fibrinogen)
What does PTT measure; what factors?
What must you add?
- Intrinsic pathway; factors XII, XI, IX, VII, X, V, II, fibrinogen
- Add negatively charged surface, phospholipids, Ca2+
(12, 11, 10, 9, 7, 5, 2, fibrinogen)
The mild bleeding tendency seen in patients with factor XI deficiency is likely explained by what?
Thrombin’s ability to activate factor V, VIII, and XI, a feedback mechanism that amplifies the coagulation cascade
Fibrinolysis is largely accomplished through the enzymatic activity of?
Breaks down what?
What is one of the breakdown products?
- Plasmin which breaks down fibrin and interferes w/ its polymerization
- Breakdown product = D-dimers
The generation of plasmin from plasminogen is accomplished how?
What is the most important plasminogen activator; when is it most active?
- By factor XII-dependent pathway
- t-PA is most important activator; synthesized by endothelium and is most active when bound to fibrin
Once activated plasmin is tightly controlled by?
α2-plasmin inhibitor
Which factors are released by the intact endothelium that inhibit platelet activation and aggregation?
- PGI2
- NO
- Adenosine diphosphatase
What do heparin-like molecules on surface of endothelium activate?
What does this do?
- antithrombin III
- Inactivates thrombin, factors IX, X, XI, XII
*clinical utility of heparin is based on ability to stimulate antithrombin III activity
What induces the release of t-PA and why is this important?
Thrombin induces release of t-PA by endothelial cells, promoting fibrinolysis
Defects of of primary hemostasis (platelet defects or vW disease) may be acquired, what are some of the causes?
- Aspirin use inhibiting cyclooxygenase –> decrease TxA2 –> decreased platelet aggregation
- Renal failure —> uremia –> decreased platelet function
- Thrombocytopenia (low platelet count): if very low intracerebral hemorrhage can occur and be fatal
What does protein C do?
What does it require the help of?
- Inactivates factors V and VIII
- Vitamin K-dependent protease that requires a cofactor, protein S
Defects of primary Hemostasis is associated with what?
Classic finding?
- Mucocutaneous bleeding (i.e., epistaxis, GI bleeding, or menorrhagia)
- Petechia (1-2mm) and purpura (4-10mm)
What is Bernard-Soulier syndrome?
- GpIb deficiency
- Defect of primay hemostasis
Defects in secondary hemostasis are due to defects in?
How do they present?
- Coagulation factor deficiency(ies) either heriditary or acquired
- Often present with bleeding into joints (hemarthrosis) or soft tissue
Hemophilia A and B are caued by deficiencies in what factors?
- Hemophilia A = Factor VIII deficiency
- Hemophilia B = Factor IX deficiency
What makes up the Virchow triad in thrombosis?
1) Endothelial injury: procoagulant changes or anti-fibrinolytic effects
2) Abnormal blood flow: stasis or turbulence
3) Hypercoagulability (AKA thrombophilia)
What occurs in Disseminated Intravascular Coagulation (DIC)?
Characteristics of DIC?
- Activation of the coagulation and fibrinolysis systems —> simultaneous production of thrombin and plasmin
- Widespread microthrombi
- Consumption of coagulation factors and platelets (AKA consumptive coagulopathy)
What do the lab studies show in DIC (PT, PTT, fibrinogen, D-dimer, platelet count)?
- Elevated PT and PTT
- Low fibrinogen
- Increased D-dimer
- Low platelets (thrombocytopenia)
Where are most coagulation factors made?
What occurs to PT and PTT with dysfunction of this organ?
- Liver
- Decreased function = decreased synthesis = elevation of PT and PTT
Vitamin K is essential for production of what important components of the coagulation system?
Factors X, IX, VII, II (prothrombin), Protein C and S
(10, 9, 7, 2, Prot. C & S)
Vitamin K deficiency is seen in?
- Patients receiving warfarin/Coumadin
- Malnourished or prolonged parental nutrition
- Prolonged antibiotics (Vit K is synthesized by gut microflora)
- Newborn infants
What is the definition of a Massive Transfusion?
What does it cause?
- Replacement of 1.5 x blood volume in 24 h
- Increased PT and PTT, decreased fibrinogen and platelets
When does endothelial dysfunction result in a prothrombotic environment?
- Chronic inflammation
- HTN
- Hyperlipidemia and homocystinemia
- Circulating toxins (from cigarette smoke)
In endothelial injury the expression of which anticoagulants are downregulated?
What are the antifibrinolytic effects?
Procoagulant effects:
- Decreased thrombomodulin (by cytokines)
- Decreased protein C
- Decreased TF inhibitor
Antifibrinolytic effects:
- Decreased t-PA (by secreted PAIs)
Arterial thrombi arise at sites of?
Venous thrombi at sites of?
- Turbulence in arteries and heart (arterial and cardiac thrombosis)
- Stasis in vein (venous thrombi)
Altered blood flow contributes to thrombosis in several clinical settings, what are some examples?
- Ulcerated atherosclerotic plaques
- Aneurysms
- Infarcted myocardial tissue
- Prolonged immobilization (bed rest)
What is the defect in Factor V Leiden; resistant to?
Most common among what population?
- Arg –> Glu substitution, increased risk for venous thrombosis
- Resistant to protein C (important counterregulatory pathway lost)
- Most common among Caucasians (2-15% have at least one mutated gene)
- 60% of patients with recurring DVT has this mutation
What is the 2nd most common inherited cause of hypercoagulability?
What gene?
Increased risk for?
- Single nucleotide change in (G20210A) in 3’-untranslated region of prothrombin gene
- Leads to elevated prothrombin and almost 3-fold increase in risk of venous thrombosis
Marked elevation of Homocysteine may be caused by an inherited deficiency of what enzyme?
Contributes to what problems?
- Cystathione β-synthetase
- Arterial and venous thrombosis, as well as development of atherosclerosis
What are some examples of secondary (acquired) hypercoagulability (list 9)?
- Immobilization (bed rest/long flights)
- MI or atrial fib
- Cancer
- Hyperestrogenic state
- Oral contraceptives
- Tissue injury (surgery, fracture, burn)
- Smoking
- Heparin-induced thrombocytopein (HIT) syndrome
- Antiphospholipid antibody syndrome
Heparin-induced thrombocytopenia (HIT) syndrome occurs following the administration of?
Induces the appearance of?
- Unfractionated heparin
- May induce the appearance of Abs that recognize complexes of heparin and platelet factor 4 on surface of platelets and endothelial cells
- Effect of the Ab binding produce a pro-thrombic state, even in the face of heparin administration and low platelet counts
What must be considered when a patient younger than 50 presents with thrombosis even when acquired risk factors are present?
Inheritable causes of hypercoagulability (factor V Leiden or prothrombin mutations)
Antiphospholipid Antibody syndrome has clinical manifestations, including recurrent?
What Ab?
Abs suspected of binding to?
Can give a false positive?
- Recurrent thromboses, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia
- Anticardiolipid antibody
- Suspected Ab targets include β2-glycoprotein I, which associates w/ surfaces of endothelial cells and trophoblasts, and thrombin
- Can give a false positive syphilis test
Depending on the vascular bed involved what are some of the clinical manifestations of Antiphospholipid Antibody Syndrome?
- Pulmonary embolism
- Pumonary HTN - from recurrent subclinical PE’s
- Stroke
- MI
- Bowel infarction
- Renal failure
Antiphospholipid Antibody syndrome can be secondary and primary, what designates these forms?
Secondary = individuals w/ well-defined auto-immune disease, such as systemic lupus erythematous
Primary = pt’s exhibit only manifestations of a hypercoagulable state
What is Migratory Thrombophlebitis (aka Trousseau’s syndrome)?
- Seen with malignant cancers (pancreatic, lung) where they reduce prothrombotic mucin
- Tumor associated inflammation and coagulation factors (TF and factor VIII), as well as procoagulants (i.e., Mucin) all increase risk of thromboembolism in disseminated cancer
Thrombi are often laminated with what morphological characteristic?
Indicates and helps distinguish how?
- Lines of Zahn: alternating red and tan regions (containing RBCs and platelets/fibrin, respectively)
- Indicating that the thrombus formed in flowing blood, helps distinguish antemorten clots from bland non-laminated clots occuring postmortem
Common sites of arterial thrombi include?
- Coronary, cerebral, and femoral arteries
- Sites of turbulence or endothelial injury
Venous thrombi are typically richer in _____ and form ______?
Venous thrombi are typically richer in RBCs and form casts
Common sites of venous thrombi include?
Veins of leg (superficial and deep), UE’s
Thrombi occuring in the heart or within the aorta are termed?
Occur in the setting of?
- Mural thrombi
- Occur in setting of MI or aortic aneurysm
In enusing days to weeks following a thrombus, the thrombi will undergo dissolution which is the result of?
How does the age of the thrombi effect this and any therapeutic ?
- Dissolution by fibrinolysis
- Older thrombi are more resistant to lysis
- Therapeutic administration of t-PA is generally effective only when given during first few hours of a thrombic event
Thrombi on heart valves are called?
Vegetations
What occurs in organization (which cell types come in) and recanalization of a thrombus?
Organization: thrombus replaced by fibroblasts, smooth muscle, and endothelial cells
Recanalization: new capillaries and small vessels grow through the structure
DIC is not a single disease, but rather, a complication arising from different causes such as?
- Sepsis
- Childbirth complications
- Massive trauma
- Malignancy
What type of cells may be found in DIC?
Intravascular hemolysis –> Schistocytes
Most common factor to be clinically significantly inhibited is?
May occur in multiple clinical scenarios, such as?
- Factor VIII (Hemophilia A)
- B-cell lymphoma/plasma cell neoplasms or Amyloidosis
A mixing study is used to determine what?
What will not correct if there is inhibitor present?
- Whether abnormal clotting times are due to a decreased amount of factor or presence of an inhibitor (i.e., an antibody)
- PTT will remain prolonged if inhibitor present
Thrombi are focally attached to the underlying vascular surface where the site of injury occured, which direction do arterial and venous thrombi extend?
Both toward?
- Artierial thrombi grow retrograde
- Venous thrombi extend in direction of blood flow
- BOTH sources of thrombi extend towards the heart
Weakening of the vessel wall that can occur from trapped leukocytes and platelets releasing lysosomal enzymes within the center of a thrombus that later becomes infected may result in _________ if unchecked?
Mycotic aneurysm
>95% of Pulmonary Embolisms arise from?
Deep venous thrombi (DVT) of the legs
In PEs what can become occluded?
How does risk of PEs change with recurrence?
- Main pulmonary artery, straddle pulmonary artery bifurcation (saddle embolus), or pass out into the smaller, branching arteries
- Patient who has had one PE is at high risk for more
Superficial venous thrombi typically occur where?
Cause what?
- Saphenous veins
- Local congestion, swelling, pain, and tenderness, but rarely embolize
- Associated edema and impaired venous drainage predispose overlying skin to development of infections and ulcers (varicose ulcers)
Deep venous thrombi typically occur in which veins?
Why are they more serious?
Symptoms?
- Popliteal, femoral, and Iliac Vs.
- Can embolize to the lung
- 50% are asymptomatic; some cause edema and pain
Sudden death or right heart failure from PE may occur when?
60% of the pulmonary arterial circulation is obstructed
Most systemic emboli (80%) arise from?
Intracardiac mural emboli (LV wall and LA dilation/fibrillation
Vast majority of arterial emboli (systemic thromboembolism) travel to and come to rest where?
Other places include?
- Majority to lower extremities (75%)
- Brain (10%)
- Others: intestines, kidneys, spleen, UE’s
What are the other sites of systemic thromboembolism?
- Aortic aneurysms
- Atherosclerotic plaques
- Cardiac valves (“vegetations”)
- Paradoxical emboli
Fat and marrow embolisms are usually caused by?
Where does it translocate?
Very common incidental finding after?
- Bone fracture (long bones), the trauma of which pushes marrow/fat globules into venous sinuses and then travesl to the lungs
- Vigorous CPR
What is a paradoxical embolism?
Venous embolus passed through defect in heart and gains access to systemic arterial circulation
What is fat embolism syndrome?
Characterized by?
What is the onset like?
- Symptomatic fat and marrow emolisms (minority of patients)
- Pulmonary insufficiency, neurological sx’s, anemia, and thrombocytopenia
- Typically 1-3 days after injury there is sudden onset of tachypnea, dyspnea, and tachycardia; irritability and restlessness can progress to delirium or coma
What causes the biochemical injury seen in Fat Embolism Syndrome?
- Release of free fatty acids from fat globules causes local toxic injury to endothelium
- Platelet activation
- Granulocyte recruitment
Air embolisms must be what size to produce a clinical effect?
How can they be introduced?
- Greater than 100cc
- Surgically (vascular, neurosurgical, or laparoscopic)
What is Caisson disease?
Most common sites?
- Persistence of gas emboli in skeletal system leads to multiple foci of ischemic necrosis
- Femoral head, tibia, and humerus
What is an Amniotic Fluid Embolism?
85% of survivors have?
- 5th most common cause of maternal mortality
- Amniotic fluid and/or fetal tissue enter maternal circulation via tear in placental membranes or rupture of uterine veins
- 85% of survivors have permanent neuro deficits
What is seen at the onset of Amniotic Fluid Embolism and is followed by?
If survived, commonly seen?
- Onset: severe dyspnea, cyanosis, and shock
- Followed by: neurologic impairment (headaches, seizure, coma)
- If survived, then pulmonary edem and frequently DIC
Histologically what kind of cells will be seen in pulmonary arterioles as a result of an Amniotic Fluid Embolism?
Fetal squamous cells
Much of the morbidity/mortality for Amniotic Fluid Embolism is caused by the biochemical activation of?
Coagulation factors and innate immune system
What is infarction?
Due to what?
- Ischemic nerosis via occlusion of arterial supply or venous drainage
- Arterial thrombosis or thromboembolism
- Less common causes include: torsion, vessel trauma, compression due to tumor or edema, and herniation
What is characteristic of a red (hemorrhagic) infarct, where are they most often found?
- Tissue with a dual blood supply (lung, small intestine)
- Venous occlusion (torsion)
- Previously congested tissue
- Reperfused necrotic tissue after arterial occlusion
What is characteristic of a white (anemic) infarct, where are they most often found?
- Arterial occlusions in solid organs with end-arterial circulation
- Spleen, kidney, or heart
What is the morphology of an infarct both macro- and microscopically?
- Wedge-shaped, involving the geographic distribution of the occluded vessel
- Ischemic coagulative necrosis; except brain = liquefactive
- Most infarct ultimately replaced by scar
What is the most common cause of death in US ICUs?
Mortality rate?
Causative organism?
- Septic Shock
- >20% mortality
- Gram positive bacteria
When does a septic infarct occur?
What can it be converted to?
- Infected cardiac valve vegetations embolize or when microbes seed necrotic tissue
- Infarct converted to an abscess w/ a correspondingly greater inflammatory response
What causes shock?
Diminished cardiac output or reduced effective circulating blood volume impairs tissue perfusion and leads to cellular hypoxia
What causes cardiogenic, hypovolvemic, and shock associated with systemic inflammation?
Cardiogenic = decreased cardiac output; MI, tamponade, arrhythmias
Hypovolemic = low cardiac output due to low blood volume; such as massive hemorrhage or fluid loss from severe burns
Sytemic inflammatory effects = microbial infections, burns, trauma, or pancreatitis; massive outporuing of inflammatory mediators (innate and adaptive) causing vasodilation, vascular leakage, and venous pooling
What are the main characteristics of septic shock (i.e., pathogenesis)?
- Microbial products (PAMPs) induce innate immune cells to release cytokines (i.e., TNF, IL-1, IFN-y, HMGB1); upregulation of endothelial adhesion molecules; activation of complement cascade; microbial components can directly activate coagulation through factor XII
- Vasodilation –> Decreased BP
- Increased permeability –> leakage and edema, impeding perfusion
- Systemic increase of thrombin –> DIC in ~50% (procoagulant state)
Hyperinflammatory state initiated by sepsis also activates counter-regulatory immunosuppressive mechanisms, what is one proposed mechanism for the immune suppression?
Shift from TH1 (pro-inflammatory) to TH2 (anti-inflammatory) cytokines
What metabolic disturbances can septic shock cause?
Inflammatory cytokines impair what?
- Insulin resistance and hyperglycemia
- Cytokines suppress GLUT-4
- Adrenal insufficiency and defecit of glucocorticoids
Cellular hypoxia and decreased ox-phos in septic shock leads to what?
Increased lactate production and lactic acidosis
How does septic shock affect organs?
The damage is occuring due to?
- Accumulated damage secondary to hypoxia
- Decreased perfusion secondary to decreased BP, vascular leakage, edema, stasis and thrombi
- Kidneys, liver, lungs (ARDS), and heart most affected
What is the treatment for septic shock?
- Treat underlying infection - antibiotics
- IV fluids, pressors, and oxygen
In the initial nonprogressive stage of shock what is occuring and the net effect/goal of these mechanisms?
- Compensatory mechanisms and perfusion of vital organs maintained by:
- Baroreceptor reflex
- Sympathetic discharge –> Catecholamines
- Renal conservation of volume (RAAS) and release of ADH
- Net effect: tachycardia, peripheral vasoconstriction, and renal conservation of fluid
What characterizes the progressive phase of shock?
- Tissue hypoperfusion and widespread hypoxia
- Aerobic —> anaerobic metabolism (lactic acidosis)
- Arterioles dilate and blood begins to pool in microcirculation (stasis)
In cardiogenic/hypovolemic shock, how does the patient present?
Septic shock?
- Hypovolemic/cardiogenic shock: hypotension, tachypnea; skin is cool, clammy, and cyanotic
- Septic shock: skin initially warm and flushed due to peripheral vasodilation
What are the group of secreted bacterial proteins that can cause a syndrome similar to septic shock, called toxic shock syndrome?
Describe them.
- Superantigens
- Polyclonal T-lymphocyte activators that induce release of high levels of cytokines
- Result in variety of clinical manifestations, ranging from diffuse rash to vasodilation, hypotension, shock, and death
Lungs are seldom affected in pure hypovolemic shock because are somewhat resistant to hypoxic injury, however what can happen to lungs if shock is caused by sepsis or trauma?
Diffuse alveolar damage, so-called shock lung
What induces conformational change to express the GpIIb-IIIa complex to be exposed?
ADP
What is the cause of nutmeg liver?
What is the cause of chronic hepatic congestion?
Chronic hepatic congestion/central vein congestion
can lead to portal HTN
Severe heart failure
