1
Q
What is edema?
A
abnormal accumulation of fluid in the interstitial space (outside of the cells) d/t disorders that disturb the function of the heart, kidneys or liver.
2
Q
What is effusion?
A
abnormal accumulation of fluid in body cavities (potential spaces) lined with serosal membranes. These spaces include: pleural space, pericardial space, joint space and peritoneal space
3
Q
What 4 places can effusion occur in?
A
1. Pleural space (hydrothorax)
2. Pericardial space (hydropericardium)
3. Joint space
4. Peritoneal space (hydroperitoneum; ascities)
4
Q
Effusion inside the peritoneal space is called what?
A
Ascites
5
Q
The fluids of edema and effusion can be categorized as what and can be ________ or _______.
A
inflammatory or noninflammatory
localized (d/t venous or lymphatic obstruction) or systemic (d/t heart failure)
6
Q
What is the difference between inflammatory and non-inflammatory related edema/effusion?
A
Inflammation-related edema and effusion:
- protein rich (exudate) due increased vascular permeability caused by inflammatory mediators
- Typically localized to a local area, but can also be systemic when the pt has sepsis
Noninflammatory edema and effusion:
- protein poor fluid (transudate) that is common in diseases that affect the pressures of the vascular system.
- Ex. <3 failure, liver failure, renal dz, nutritional disorders.
7
Q
How do we normally prevent edema and effusion?
A
- Normally; the balance of fluid movement is kept equal;
- an increase in hydrostatic pressure pushes fluid out or decrease in colloid osmotic pressure => increase in interstitial fluid.
- If the amount of fluid in the interstial space > lymphatic drainage
- => fluid will accumulate.
8
Q
What are the causes of non-inflammatory edema (4)
A
- 1. Increased hydrostatic pressure
- 2. Reduced plasma oncotic pressure
- 3. Na and Water Retention (often d/t renal failure)
- 4. Lymphatic obstruction
9
Q
Describe how increase hydrostatic pressure => non-inflammatory edema
A
Forces fluid out and is most often d/t impaired venous return (congestion). Increased hydrostatic pressure can be localized (ex DVT) or systemic (CHF; causes a wide-spread increase in hydrostatic pressure). This can occur by 3 mechanisms:
- Congestion* => passive PATHOLOGICAL CONDITION where not enough blood is leaving, causing a backup of venous blood in the capillary beds => fluid leaks out.
- Na/H20 rentention => the overall volume
- Hyperemia => active physiological arterial condition where arterial dilation=> too much oxygenated blood is arriving at the tissue => tissue turns red
- This can be controlled by pre-capillary sphincters, which maintain appropriate pressure.
10
Q
What 3 mechanisms can cause increased hydrostatic pressure, which leads to edema?
A
- Congestion=> a passive pathological condition where blood is not leaving, causing a backup of VENOUS blood. This venous blood increases hydrostatic pressure => leaks out => edema
- Hyperemia=> a active physiological condition where too much oxygenated arterial blood is arriving in normal conditions d.t dilation. This is controlled by pre-capillary sphincters, which help to maintain app pressure. Ex. is running => incrase BF to face
- Na and H20 retention => nicreases overall volume
11
Q
- A passive pathological condition where not enough blood is leaving, causing a backup of venous blood in the capillary beds.
- As a result, fluid leaks out of the BV -> edema,
- Is this condition local or systemic?
A
Congestion
Can be local or system
12
Q
- a physiological arterial condition where too much blood is arriving at the tissue d/t dilation -> causing tissue to turn red
- Is this condition local or systemic?
A
Hyperemia
Condition can be both
13
Q
Describe how reduced plasma oncotic pressure => non-inflammatory edema.
A
- In normal circumstances, albumin accounts for almost half of the total protein in the plasma. It wants to keep fluid in.
- Decrease albumin => decrease oncotic pressure .
- Loss of albumin and decreased plasma oncotic pressure can be d/t:
14
Q
Albumin helps to regulate our plasma oncotic pressure. How can we decrease these levels => non-inflammatory edema?
A
Altering the amount MADE (cirrhosis or protein malnutrition) or increasing the amount loss (nephrotic syndrome)
- Liver diseases (cirrhosis): not enough proteins made
- Protein malnutrition: not enough intake of proteins -> not synth new albumin
- Kidney disease with nephrotic syndrome: too many proteins lost through filtration.
*
- Kidney disease with nephrotic syndrome: too many proteins lost through filtration.
15
Q
What is the process that causes non-inflammatory edema if we have a decrease in plasma oncotic pressure?
A
- 1. Proteins are lost
- 2. Net movement of fluid into the tissue (interstitiam) from the blood
- 3. Decrease renal perfusion => + RAAS system
- 4. Attempts to hold onto Na+ and water, however, this cannot correct the deficit because we have a deficit of proteins
16
Q
Describe how Na+ and water retention can cause non-inflammatory edema?
A
Causes BOTH: increase hydrostatic pressure and decreased osmotic pressure
- Disease => Decrease renal perfusion => activation of RAAS system =>
- Increased salt retention: increases volume of vascular system, which increase the hydrostatic pressure AND decrease in the plasma colloid pressure d/t dilution.
- Activation of RAAS system is good at first to improve CO and restore normal perfusion. However, as the <3 worsens, Na+ and water retention => edema and effusion
17
Q
Describe how lymphatic obstruction can cause non-inflammatory edema?
A
- Trauma, fibrosis, invasive tumors, and microbes => lymphatic obstruction => lymphedema
- Lymph system cannot to take up the fluid => LOCALIZED EDEMA called lymphedema
18
Q
Lymphedema can be seen in what 2 conditions?
A
- Filariasis (helminth infection/Wucheria): round worm infection that causes unilateral localized lymphedema.
- Obstructive fibrosis => edema of the external genitalia and lower limbs that can be very extreme and called elephantiasis.
- In the U.S, unilateral lymphedema is most commonly seen in breast cancer patients who have received axillary LN removal.
- Causes severe edema of the area (arm) that the LN drained
19
Q
- What is the morphology of edema?
- What do the organs look like?
- What is the morphology of edema?
A
- Subcutaneous edema
- Pulmonary edema
- Brain edema
Organs will look large and heavy
20
Q
Describe subcutenaous edema.
A
Subcutaneous edema can be diffuse or it can occur in _areas with high hydrostatic pressur_e.
- Hydrostatic pressure => influenced by gravity (thus, called dependent edema)
- When standing => hydrostatic pressure is greatest in legs => edema in legs
- When laying down => hydrostatic pressure is greatest in sacrum => edema in sacrum
Pressure over subcutaneous edema can leave a depression called pitting edema.
21
Q
Subcutaneous edema raise what suspicions for the doctor from the patient?
A
- 1. Cardiac disease
- 2. Renal disease
- When significant, it can impair [wound healing and clearance of infection].
22
Q
Describe how cardiac failure can cause edema.
A
- Cardiac failure can cause pitting edema, pulmonary edema and pulmonary effusion
- . In <3 failure, we see a decrease in pumping activity of the heart;
- Congestion in the lungs d/t left ventricular failure -> congestion in pulmonary venous circulation -> backflow of blood-> pulmonary edema and pleural effusion
- Fluid collects in the alveoli septa and around capillaries and impedes O2 diffusion. Edema fluid in alveolar spaces creates a favorable environment for bacterial infection.
- In pulmonary edema, the lungs are 2-3X their normal weight and will give off a suctioned fluid that is frothy and a mixture or air, edema, and RBCs
- Pulmonary effusion often accompany pulmonary edema and can compromise gas exchange by compressing pulmonary parenchyma.
- Increases capillary hydrostatic pressure -> edema
- Decrease in blood to kidneys -> + RAAS -> retention of Na+ and H20 -> increase in blood volume -> increases hydrostatic pressure and decreases oncotic pressure -> edema
- Congestion in the lungs d/t left ventricular failure -> congestion in pulmonary venous circulation -> backflow of blood-> pulmonary edema and pleural effusion
23
Q
Describe how renal failure can cause edema.
A
Renal failure can cause edema in two ways:
- Retention of Na+ and water -> increases in blood volume -> increase in intravascular hydrostatic pressure ->edema
- Nephrotic syndrome -> glomerulus are damaged, causing an excess of protein loss in the urine -> decreases oncotic pressure -> edema
- Edema from renal failure initially appears in parts of the body that contains loose CT: like the eyelids (periobital edema) and is a characteristic sign.
24
Q
Pt John comes in with begining renal failure. Where is the first place he will begin to see edema?
A
Renal failure => hypoproteinemia => parts of his body w/ loose CT, such as his eyes (periorbital edema).
25
What does **brain edema** cause?
LIFE THREATENING =\> will cause the brain to have narrowed sulci and distended gyri due to compression of the skull.
If severe, **brain can herniate through foramen magnum or compress vasculature in brainstem**
26
* **Peritoneal effusion (ascities) i**s most commonly due to \_\_\_\_\_\_\_\_\_\_\_.
* Any other causes?
* What should we tell the patient that they are more prone to?
Ascites is most commonly d/t liver disease, which causes **portal hypertension.**
* _d/t decreased production of albumin._
Patients with acities will be at increased risk for: **BACTERIAL INFECTIONS!**
27
_effusions_ involving the pleural cavity
**Hydrothorax**
28
effusions in the pericardial cavity
**Hydropericardium**
29
* effusions in the peritoneal cavity.
**Hydroperitoneum (ascites):**
30
* [Q:] What kind of fluid is escaping the intravascular compartment?
1. **Exudate**: _protein-rich_ and will look _cloudy_ because it has blood cells. Inflammation will increase space between endothelial cells, cause vasodilation and stasis =\> forming exudate.
2. **Transudate**: _protein-poor, serous and water fluid_ caused by an increase in hydrostatic poressure (venous outflow struction) and decreased plasma oncotic pressure. An **_exception would by chylous effiusion,_** ascites caused by lymphatic blockage. It will be _milky d/t presecend of lipids_ that are absorbed in the gut.
31
[Q:] Describe the events of liver failure.
* Liver failure can result in **edema** and **ascites**.
* **Liver cell failure** =\> decreased production of albumin in the liver -\> ascites and edema
* **Portal HTN causes congestion** -\> ascites in the peritoneal cavity (abdomen)
*
32
* **Hyperemia** and **congestion** are a result of what?
* Hyperemia and congestion are a result of increased blood volumes in tissues (local or systemic) =\> increase in hydrostatic pressure.
33
What is **chronic passive congestion?**
**Chronic hypoxia** (because venous blood is deoxygenated) causes congestion to become chronic =\> this causes
* Capillaries to rupture and BCs begin to leak out and causes **_hemosiderosis_**.
* After a while, this can result in i_schemic tissue injury and scarring._
* Hemosiderosis: BCs leak out, get ingested by macrophages, creating **hemosiderin-laden macrophages (aka heart-failure cells)** on histo.
34
What cell will someone with **chronic congestion** have on histolofy?
You can see hemosiderin-laden macrophages;
BVs broke, BC leaked out and were ingested by macrophages, creating **hemosiderin-laden macrophages (\<3 failure cells)**
35
What will **congested tissue** look like?
* **Tissue is blue (cyanotic)** due to RBC stasis. (lack of O2)
* **Cappilares and veinsa re are engorged,**
* **Extraversed RBCs** in interstitial tissue
36
* What is the difference between **acute pulmonary congestion** and **chronic pulmonary congestion?**
*
**Acute pulmonary congestion:**
* Alveolar capillaries are congested =\>
* Alveolar septal edema and focal intraalveolar hemorrhage
**Chronic pulmonary congestion**
* CHF causes _fibrotic septa,_ resulting in _chronic pulmonary congestion_ and alveoli will have _hemosiderin-laden macrophages._
37
What is the difference between **acute hepatic congestion** and **chronic hepatic congestion?**
**Acute hepatic congestion:**
* Central vein and sinusoids are engorged with some death of central hepatocytes.
**Chronic passive hepatic congestion**
* Chronic passive hepatic congestion is most often caused by **right \<3 failure =\> venous occulusion =\> obstruction of central vein (blood cant leave)** =\> **nutmeg liver (liver failure)**
* Nutmeg liver has a pattern of _centrilobular necrosis_: _Centrilobular hepatocytes_ are _red-brown_ d/t congestion (ischemic necrosis) since they are distal to the blood supply (receive less blood in the first place), compared to the surrounding, _tan hepatocyte_s (which may only undergo a fatty change)
38
What is **hemostasis**?
**formation of a blood clot at an injury**
39
* If **hemostasis (clot formation)** damaged, can result in:
* 1. **Hemorrhagic disorder:** Excessive bleeding where the normal hemostatic cannot stop bleeding
* 2. **Thrombotic disorders**: blood clots (thrombi) form in _blood vessels_ or in _chambers in the heart_
* 3. **Disseminated intravascular coagulation (DIC**) =\> pathological activation of coagulation cascade when not necessary, which can lead to both the formation of thrombi problem and excessive bleeding (IV areas and mucosal surface) when we do need to clot since the excessive clotting is using up all of the clotting factors
40
What are the basic steps of **hemostasis**?
* 1. Arteriole vasoconstriction d/t neural stimulation and endothelin released from endothelial cells.
* 2. Primary hemostasis: formation of a weak platelet plug (adhesion =\> activation =\> aggregation).
* 3. Secondary hemostasis: formation of a stabile platlet plug by depositing **fibrin**
* 4. Stop hemostasis: stop forming the clot, resorption of clot and repair tissue.
41
Describe the process of **primary hemostasis,** formation of a weak platelet plug.
**_DAMAGE TO THE ENDOTHELIUM:_**
**1.** **Transient vasoconstriction** d.t neural impulses and endothelin released from endothelium
2. **Adhesion**: Damage to the endothelium reveals a basement membrane filled with collagen and subcutaneous tissue filled with collagen.
* Weibel Palade bodies in endothelial cells and alpha-granules of platelets fuse with the plasma membrane =\> uncoil =\> release vWF.
* vWF binds to the exposed subendothelial collagen
* GP1b on the platelets bind to the vWF on the collagen, initiating activation.
3. **Activation**: Adhesion then causes activation, which is:
* _Change in shape:_
* _P_latelets from flat -\> spikey to increase SA,
* Translocation of negatively charged phospholipids onto the surface of the platelets
* _Degranulation_ of alpha and dense granules with the release of ADP and TxA2).
* Triggered by: _thrombin,_ _ADP_, and _TxA2_
* Thrombin activates other platelets by cleaving PAR (protein-activated receptor).
* Activation and ADP promote _recruitment (activation of more platelets)_
* ADP is released from dense granules =\> causes more activation and exposes GPIIb/IIIa receptors on platelets-\> increasing affinity for fibrinogen /
* _Thromboxane_ A2 is made by platelet COX =\> promote aggregation.
* Platelet activation and ADP promotes more platelets to be activated in a process called recruitment.
4. **Aggregation**: Aggregation of platelets is promoted by ADP and TxA2 at the site of injury by linking GP2b/3a complexes from different platelets together using fibrinogen released from the plasma =\> forming a primary hemostatic plug.
42
Describe the process of **secondary hemostasis,** deposition of fibrin to form a stable, insoluble fibrin clot
**What happens:** Coagulation cascade converts [_prothrombin -\> thrombin]_, which converts the [_fibrinogen -\> fibrin_], stabilizing and making the clot insoluble.
1. Originally, clotting factors (_made by the liver) ARE INACTIVE_
2. Activation of the factors requires:
1. _Exposure to an activating substance_
1. Extrinsic pathway: tissue factor (**TF**) activates **factor 7**
2. Intrinisic pathway: **negatively charged surface on platelets activates factor 12.**
2. _Presence of subendothelial collagen_
3. _Ca2+_
3. End product: formation of insoluble fibrin clot
43
Describe the **extrinsic and intrinsic pathway** that occurs in **secondary hemostasis.**
**Tissue factor** is released when endothelial cells are damaged at the site of injury, activating the extrinsic pathwa.y
44
What is **tissue factor?**
A **procoagulant glycoprotein** that is formed on the surface of subendothelial cells whe injury occurs and activates the extrinsic pathway of the coagulation cascade.
45
How do we measure the extrinsic and intrinsic pathway and combined pathway.
* **Extrinsic pathway**: _prothrombin time (PT) assay_ assess the function of the proteins in the extrinsic pathway (factors 7)
* Add tissue factor
* Clotting should occur in 10-14 seconds.
* **Intrinsic pathway**: _partial thromboplastin time (aPTT_) assess function of the proteins in the intrinsic pathway (factors 8, 9 and 11).
* Not associating with: factor 7, prekallikrein, high molecular weight kininogen, lupus anticoagulants.
* Add negative surface and Ca2+
* Clotting should occur in 32-45 seconds
* **Combined abnormal APTT and PT:** problem in the common pathway
* Medical conditions: anticoagulants, disseminated intravascular coagulation (DIC), liver disease, vit. K deficiency, massive transfusion
* Rarely dysfibrinogenemia; factor 5, 10 and 2.
46
Each step in secondary hemostasis involves what 3 things?
* 1. **Substrate**: inactive factor
* 2. **Enzyme**: activated factor
* 3. **Cofactor**: reaction accelerator
47
Where does **secondary hemostasis** occur?
**On the negative phospholipid surface of activated platelets.**
48
**[Q:] How do we stop clot formation/restrict it to the site of injury?**
1. **Normal healthy endothelium** covers tissue factor, which prevents coagulation
2. Factors are only **activated AT the site of injury** d/t presence of neg. phospholipids
3. **Dilution with increased blood flow** washes out activated clotting factors
4. As **fibrin** covers up the platelet surface, no more coagulation can occur on the platelet
5. **Fibrinolysis** dissolves clot after it heals via plasmin (endogenous fibrin dissolver)
* _{Plasminogen -\> plasmin via tPA or factor XII–dependent pathway]_ =\> dissolves clot
* _a2-plasmin inhibitor_ inactivates plasmin
* tPA comes 4rm endothelium and most active when bound to fibrin
* As we break bown fibrin clots =\> _increase number of D-dimers (breakdown products)_ =\> marker for thrombotic states
*
49
What are the vitamin-K dependent factors and how are they activated?
2, 7, 9, 10, protein C and S.
* **Vitamin K dependent carboxylation** must occur to bind Ca2+ =\> activate factors 2, 7, 9 and 10
50
What is **coumadin**?
**Coumadin (warfarin)** is a **anticoagulant** that blocks Vitamin K dependent decarboxylation =\> Ca2+ cannot bind to factors 2, 7, 9, 10, protein C and S =\> factors are not activated =\> **coagulation does not occur.**
51
What are the names of **factors 1, 2 and 8?**
**1= fibrinogen/fibrin**
**2= prothrombin/thrombin**
**8= antihemophillic A factor (AHF)**
52
What are hemorrhagic disorder?
**Hemorrhagic disorders** are disorders of the _vessel walls,_ _platlets_ or c_oagulatio factors_. They include primary hemostasis disorders, secondary hemostasis disorders that cause bleeding.
53
The clinical significance of **hemorrhage** depends on what?
1. **Volume** of the bleed
2. The **rate** at which it occurs
3. **Location** of the bleed
54
Compare and contrast complications of **acute, severe hemorrhage with chronic blood loss.**
* 1. **Acute (rapid)** loss of blood can have little effects on adults if small, however larger amounts can cause _hypovolemic (hemorrhagic) shock._
* 2. Bleeding in subcutaneous tissue may be inconsequential, but if it occurs in the brain (_intracranial hemorrhage_), it can cause death.
* 3. **Chronic EXTERNAL blood loss** (d/t peptic ulcer or intracranial bleeding) =\> iron loss =\> anemia; however _if the blood is not lost to the external environment_ =\> the iron is recovered and recycled and used to make Hb.
55
**Primary hemostasis disorder** are often due to what?
**_Abnormalities in the_ _platelets_: they can either be**
1. Quality of the platelets
2. Number of platelets
* **Thrombocytopenia**: decreased in the number of platelets
56
What clinical features are most common of **primary hemostasis?**
1. **Mucosal bleeding:**
1. Epistasis (nose bleeding)\*
1. most common
2. GI bleeding
3. Excessive mensutration (menorrhagia)
2. **Easy bruising and skin bleeding:**
1. Petachiae (\< 3mm)
2. Purpura (\>3mm: larger)
3. Ecchymoses (palpable)
3. ***Excessive thrombocytopenia* can cause intracranial bleeding**
57
What are examples of disorders of HEREDITARY **primary hemostasis**?
What about ACQUIRED
Hereditary
* **1. Von Willebrand disease**
* **2. Bernard Soulier syndrome**
* **3. Glanzmann thrombasthenia**
Acquired**: ASP inhibits COX (which makes TXA2)** or **renal failure.**
58
What is a **von Willebrand disease?**
von Willebrand disease is a **primary hemostatic _adhesion_ disorder.** It is the most **_common inherited coagulation disorde_**r caused by a **decrease number of vWF** =\> problems with platelet adhesion =\> mild skin and mucosal bleeding.
59
**What lab results will be see in a patient with vWF?**
* _____ Bleeding time
* _____ PTT
* ____ PT
* ____ ristocetin test
* **Increased bleeding time**
* **Increased PTT**
* Because vWF helps to stabilize factor 8.
* If decreased vWF =\> decrease factor 8, however we show no symptoms of secondary hemostatic disorders.
* **Normal PT**
* **Abnormal ristocetin test:**
* Ristocetin causes platelet aggluttination by causing [vWF to bind to G1Pb]. Lack of vWF =\> abnormal agluttination=\> abnormal test
60
What is **Bernard Soulier syndrome?**
a **primary hemostatic _adhesion_ disorder** caused by a _lack of GP1b receptors on platelets_, which impaired adhesion during primary hemostasis.
61
What is **Glanzmann thrombasthenia?**
Glanzmann thrombasthenia is a **primary hemostatic _aggregation_ disorder** caused by a **deficiency in GPIIb/IIIa complexes =\>** impairs platelet aggregation.
62
Both Bernard Soulier syndrome and von Willebrand disease are adhesion disorders that cause a defect in primary hemostasis.
## Footnote
**How do we differentiate them on peripheral smear?**
Bernard Soulier syndrome (lack of GP1b receptor) will have **GIANT platelets o**n a smear.
63
A patients who overdoses o**n aspirin (NSAIDs)** will experience what problems?
**NSAIDS =\> inactivate COX =\> decrease in thromboxane A2 =\> _decrease in aggregation of platelets_**
64
**Disorders of secondary hemostasis** are usually due to \_\_\_\_\_\_\_\_\_.
What are the **clinical features?**
* Disorders of secondary hemostasis**:** are due to **factor abnormalities** that are heriditary or acquired =\> **problems with coagulation**
* Clinical features:
* **Deep tissue bleeding into muscles and joints (hemiarthrosis)**
* **Rebleeding** after surgery
* Intracranial bleeding can occur
65
**Secondary hemostasis disorders** are caused by factor deficiencies/dysfunction that result in prolongation of \_\_\_\_\_\_\_\_\_.
**PTT and/or PT**
66
What are acquired secondary hemostasis dirsorders?
Heriditary?
Acquired
* **1. DIC**
* **2. Liver disease**
* **3. Vit K deficiency**
Heriditary
* **Hemophilia A**
67
What is **DIC**?
What lab findings do we see? platelet count, PT/PTT, fibrinogen, other
DIC: patholothigic activation of the coagulation cascade that is almost always secondary to another disease. This causes
* 1. **Microthrombi in blood vessels,** which will cause ischemia and infarction in tissues.
* 2. Because we are using up our platelets, it will **cause bleeding**, especially from IV sites and mucosal surfaces.
1. Decreased platlet count (bc making thrombi)
2. Increase PT/PTT
3. Decrease fibrinogen (bc making fibrin clots)
4. _Anemia_
5. _**High D-dimer \* BEST TEST FOR DIC**_
68
**Vitamin K deficiency** would cause what?
**Impaired coagulation d/t decreased fx of factors 2, 7, 9, 10, protein C and S.**
Vitamin K is _made by bacteria in the gu_t and _activated in the liver._ This, this is seen in:
1. **Newborns**: lack bacteria in gut. Thus, at birth, vitK is given to child
2. **Long-term ABX**: disrupts bacteria in gut
3. **Malabsorption**: deficiency in fat-soluble vitamins.
69
What is **heparin**?
Heparin is an **anticoagulant** that **acts on the intrinsic pathway to prevent the formation of clots, but does NOT actively lyse them.**
70
What is **heparin-induced thrombocytopenia?**
## Footnote
**How do we treat?**
**Heparin can cause thrombocytopenia (a decrease in the number of platelets).**
1. Unfractioned Heparin forms a complex with platelet factor 4 [HEP-PF4] =\> produces IgG.
2. IgG will consume platelets by the spleen by recognizing [HEP-PF4]
3. Fragments of the destroyed platelets will go into the cirulation and activate remaining platets = forming a blood clot (thrombus).
4. Thisl, combined with damage endothelium =\> prothrombotic state.
**Tx**: _Anti-coagulant that is not coumadin_.
71
_Liver failure_ affects ________ **hemostasis**. How?
How do we measure affects?
Liver failure affects **secondary hemostasis.**
* The liver makes our clotting factors (proteins) and activates vitamin K =\> decreased clotting factors and decrease vitamin K =\> less activation of factors.
Measure with: **PT**
72
Describe Hemophila A.
73
How can we differentiate disorders of fibrinolysis from DIC?
**In both, we will see increased bleeding.**
However, in disorders of fibrinolysis, fibrinolysis is occuring even though there is not clot to cleave. Thus, we will have excessive cleavage of serum fibrinogen, WITHOUT an increase in D-dimers.
74
What is the difference between **chronic passive liver congestion** and **portal hypertension?**
**Chronic passive liver congestion:** Nutmeg liver that caused by central venous congestion d/t right heart failure\* (or thrombosis). This will cause necrosis of liver cells.
* Venous occlusion =\> portal vein congestion (decrease blood to liver) =\> liver disease.
**Portal HTN:** liver disease occurs first and then portal vein congestion 2nd.
75
What is important for forming the **primary platelet plug** and are the **surface where activated coagulation factors bind?**
**Platelets**
76
Injury and disorders of **small vessels** often present with
**“palpable purpura”** and **ecchymoses**, which can create a hematoma.
77
Platetes are derived from \_\_\_\_\_\_\_\_\_\_\_, which are located where?
* **Megakaryocytes** are located in the **bone marrow.**
* They send projections into blood vessels, where the platelets then bud off and flow away.
78
How does our body know to convert fibrinogen?
**Thrombin stimulates the conversion**
79
When **plasmin** is activated by tPA. What does it do?
Plasmin is a anti-coagulant (wants to prevent clots)
## Footnote
**1. Cleaves fibrin and serum fibrinogen to prevent future clots**
**2. Destroys coagulation factors**
**3. Blocks platelet aggregation**
80
When is **tPA** most active?
tPA (tissue plasmin- activator) most active **when bound to fibrin**.
* This characteristic _makes t-PA a useful therapeutic agent,_ since its fibrinolytic activity is largely confined to sites of recent thrombosis.
81
What regulates **plasmin**?
tPA;
## Footnote
Once activated, plasmin is in turn tightly controlled by counterregulatory factors such as **α 2 -plasmin inhibitor,** a plasma protein that binds =\> inhibts free plasmin [decrease in the breakdown of clots]
82
10.List and discuss the activities of **thrombin**.
* 1. Converts fibrinogen =\> cross-linked fibrin
* 2. Amplifies coagulation process, by _activating factor 11 and cofactors 5 and 8_.
* 3. Stabilizes secondary hemostatic plug by activating factor 13 (fibrin-stabilizing factor)
* 4. Activates platelets via protease-activated receptors (PARS)
* 5. **Pro-inflammatory effects**: PARS are also expressed on inflammatory cells, endothelium and other cells types.
* Activation by thrombin mediates pro-inflammatory effects =\> helps with tissue repair and angiogenesis.
* 6. **Antithrombotic functions:**
* When thrombin encounters normal endothelium: changes from a procoagulant =\> anticoagulant. This prevents clotting in other places besides site of injury.
83
**Thrombin** has what 2 kinds of effects: describe them.
**Pro-inflammatory effects and antithrombotic functions:**
* Pro-inflammatory effects: PARS are also expressed on inflammatory cells, endothelium and other cells types.
* Activation by thrombin mediates pro-inflammatory effects =\> helps with tissue repair and angiogenesis.
* Antithrombotic functions:
* When thrombin encounters normal endothelium: changes from a procoagulant =\> anticoagulant. This prevents clotting in other places besides site of injury.
84
a. Types and functions of **cytoplasmic granule**s in platelets
* **α-Granules** have the adhesion molecule _P-selectin_ on their membranes ( Chapter 3 ) and _contain proteins involved in coagulation_, such as _fibrinogen_, _coagulation factor V, and vWF,_ as well as p_rotein factors that may be involved in wound healing_, such as _fibronectin_, _platelet factor 4 (a heparin-binding chemokine_), platelet-derived growth factor (_PDGF_), and transforming growth factor-β (TGF-B)
* **Dense (or δ) granule**s contain adenosine diphosphate (_ADP_) and _adenosine triphosphate,_ ionized _Ca2+, serotonin, and epinephrine._
85
What do **Protein C and S** do?
Low protein C and S will do what?
They are **anti-coagulants,** inactivating f**actor _5a and 8a_**
* Deficiency will cause **increased risk of venous thrombosis.**
86
**Describe the action of the following**
1. PGI2
2. NO
3. ADP
4. Heparin-like molecules
5. tPA
6. Thrombomodulin
1. **PGI2** prevents platelet aggregation (opposite of thromboxane A2)
2. **NO** causes vasodilation
3. **Heparin-like molelcules** bind to anti-thrombin III (ATIII), which inactivate thrombin and coagulation factors (9a, 10a, 11a, 12a)
4. **tPA** activates fibrinolysis.
5. **Thrombomodulin**: causes thrombin to activate protein C (which requires vitamin K and protein S) =\> inactivates factor 5 and 8 =\> turns off coagulation
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12.Describe the **potential antithrombotic influence of the endothelium**, and specifically describe the mechanisms by which the endothelium exerts this influence.
Typically, the **endothelium is anti-thrombotic (preventing random thrombosis) by:**
* 1. Blocking exposure to **subendothelial collagen** and tissue factor (**TF**)
* 2. Produced **PGI2,** **NO** and **ADPase (prevent activation of platelets)** , which causes vasodilation and inhibits aggregation of platelets
* 3. Secretes **heparin-like molecules**, which bind to _anti-thrombin III (ATIII)_, which inactivate thrombin and coagulation factors (factor 9a, 10a, 11a and 12)
* 4. Secretes **tPA**, which converts activate fibrinolysis: [plasminogen -\> plasmin], which will then cleave fibrin, serum fibrinogen, coagulation factors and blocks platelet aggregation
* 5. Secretes **thrombomodulin**, which redirects thrombin to activate Protein C, which inactivates factor 5 and 8 =\> turns off coagulation.
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What is a **_thrombus**_ and a _**embolus_?**
Where do they occur and most common location?
**Thrombus**: pathological formation of an intravascular blood clot at a _particular site_ in a _artery or a vein._
* The most common location is in the _deep veins (DVT) of the leg,_ below the knee
**Embolus**: a traveling occlusion (solid, liquid or gas) that causes blockage where it lands and its s_ymptoms depend on where it lands._
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**How do we know if the clot is what killed the patient?**
**What do antemortum and post-mortum look like?**
**We need to determine if the clot occurred before death or after death.**
* If the clot occured before death (**antemortum**), it will have [_lines of zahn_: alternating layers of pale areas (_platelet_/_fibrin_) and red areas (RBCs)] and be [_attached to the wall of the vessel_].
* Thus, is the COD of the patient.
* **Post-mortum** (pooled blood) clots are
* JELLatinous (think of grape jelly),
* have a dark red portion depending on where the RBC pooled by gravity
* yellow "chicken fat" portion.
* _do NOT attach to BV._
90
**Virchows triad** are the _MAIN abnormalities that cause **thrombosis**_. What are they?
1. **Endothelial injury**
2. **Stasis or turbulent blood flow, which can cause damage to the endothelium**
3. **Hypercoagubility**
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How does **_damage to the endothelium_** lead to the formation of a thrombus?
Direct injury, infection, inflammatory mediators, hypercholesterol, smoking and turbulent BF =\> damage endothelium.
* Damage to endothelium causes it to go from being [anti-thrombotic -\> pro-thrombotic]:
* _decrease in NO a_ctivity =\> activate the endothelium =\> increase adhesion molecules =\> downregulate thrombomodulin =\> downregulate activated protein C =\> coagulation =\> thrombus
* Secretes **plasminogen activator inhibitors (PAIs)** =\> down regulates _tPA_ =\> _limit fibrinolysis_
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How do **alterations in normal blood flow** lead to thombosis?
* Normally, blood flow is continuous and laminar, keeping _platelets inactivated and dispersed._
* **Turbulence** can cause arterial and cardiac thrombosis by damaging endothelium, as well as by forming countercurrents that contribute to local pockets of stasis.
* **Stasis** is a major cause of venous thrombi.
* They both increase risk for thrombosis by:
1. **Activating the endothelium**, which causes procoagulation and leukocyte adhesion.
2. Bringing **platelets** into **contact** with **endothelium**
3. **Prevent washout and dilution of clotting factors**.
4. **Prevents influx of clotting inhibiting factors**
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* When would alteration in normal blood flow occur?
* 1. At **bifurcations**.
* Bifurcations are more prone to damage d/t atherosclerotic plaque formation =\> causes even more turbulence
* 2. Ulcerated atherosclerotic plaques not only _expose subendothelial vWF and tissue factor but also cause turbulence._
* 3. _Dilated vessels (aneurysms and hemorrhoids) =\> stasis_
* 4. Int_ernal obstruction_
* 5. _External interference/compression_
* \<3 attack can compress coronary arteries
* _6. Inadequate heart chamber fuction_
* A-fib can cause _stasis_
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What is **hypercoagubility**?
* also called **thombophilia**
* Any disease of the coagulation cascade that makes it more likely for thrombosis to occur.
95
What is the classic presentation of a hypercoaguble state?
**Recurrent DVT or DVT at a a young age.**
96
What are **primary hypercoagubility diseases?**
Primary hypercoagubility diseases are **_GENETIC_ and increase risk for thrombosis.**
* **1. Factor V Leidin**
* **2. Prothrombin gene mutation (prothrombin G20210A mutation)**
* **3. Protein C and S deficiencies**
* **4. Antithrombin III deficiency**
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What are **secondary hypercoagibility diseases?**
Secondary hypercoagibility diseases are **_ACQUIRED_ and increased risk for thrombosis.**
1. **Heparin-induced thrombocytopenia**
2. **Antiphospholipid syndrome**
3. **Oral contraceptive use**
4. **DIC**
5. **Prolonged bed rest or immbolization.**
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**_Factor V Leiden mutation_**
* **Factor V Leidin mutation is THE MOST COMMON GENETIC HYPERCOAGUOPATHY:**
* common in ppl with **_DVTs_**, particulary **_Caucasions_**.
* Mutation: Arg =\> Glu substitution in AA 506 causes **factor 5 to be resistant to cleavage by protein C** =\> thrombosis.
99
How can we test **Factor V Leidin mutation?**
* 1. Genetic testing
* _2. APC (activated protein C) restistance testing_: measure the clotting time before and after APC is added to blood sameple that is clotted with snake venom.
* **Those + are resistant to APC and clotting time plateaus.**
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**Prothrombin gene mutation (prothrombin G20210A mutation)**
* Single nucleotide change (**G20210A**) in the 3’-untranslated region that leads to _HIGH prothrombin levels_ =\> increase thrombin =\> **increased risk of _venous_ thrombosis.**
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**Deficiencies in protein C and S lead to what?**
What do they do normally?
* Deficiency in protein C and S decrease negative feedback on the coagulation cascade. Normally, they inactivate factor 5 and 8.
* Decrease in protein C and S =\> _high factor 5 and 8_ and i_ncreases risk for warfarin-skin necrosis_ =\> **hypercoagulation**.
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What is **heparin induced thrombocytopenia?**
**Heparin** can cause _thrombocytopenia_ (a decrease in the number of platelets), creating a pro-thrombotic state when combined with endothelial damage.
1. **Unfractionated heparin** forms a complex with platelet factor 4 [HEP-PF4] =\> produces IgG.
2. IgG crosslinks [Fc receptor on the platelet and the HEP-PF4 complex]
3. Causes increased production of platelet factor 4, platlet activation and aggregation =\> thrombosis =\> decreasing number of platelets
4. **=\> prothrombotic state when combined with damage to endothelium**
Tx: Anti-coagulant that is not coumadin.
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What is **warfarin skin necrosis?**
Patients with deficiencies in protein C and S have an increase risk for **warfarin skin necrosis.**
* **Coumadin blocks expoxide reductase in the live**r =\> cant activate Vit K =\> decreases activation of factors 2, 7, 9, 10, protein C and S.
* Thus, if we give a patient with low protein C and S coumadin (without another anti-coagulant)
1. Decreased production of new 2, 7, 9, 10, C and S.
2. Old factors willl then start to decrease: Protein C and S are the first to degrade because they have the shortest 1/2 life.
3. Thus, depletion of anti-coagulants occurs 1st because we are already low on C and S.
4. When anti-coagulants (C and S) are gone, pro-coagulants (2, 7, 9 and 10) are present without an anti-coagulant =\> increases risk for activation
5. Increase activation of pro-coagulants =\> increases risk for formation of a thrombus (hypercoaguble state), especially in the skin.
**THUS; patients on coumadin are also given heparin to prevent clot formation until 2, 7, 9 and 10 are destroyed.**
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What is **_antiphospholipid antibody syndrome?_**
* An autoimmune disease where patients produce of **antiphospholipid antibodies**, which attack phospholipids in cell membrane and proteins bound to the phospholipids (damage membrane) to produce a _hypercoagulable state (thrombotic)_. There are 2 forms:
* **Primary**: antiphosholipid AB syndrome occurs alone, without any other autoimmune disease
* **Secondary**: occurs with another autoimmune disease, especially lupus.
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What are the clinical manifestations of **antiphospholipid AB syndrome?**
**Hypercoagulable state**, which can cause _recurrent arterial/venous thrombosis_ and _miscarriages or stillbirth._
* Arterial thrombosis can cause _\<3 attack, stroke or limb ischemia_ (bc decrease in O2 delivary)
* _Mitral valve vegetations_
* Venous thrombosis can cause DVT.
* Part of a DVT can break off and cause an embolism in the lungs _(pulmonary embolism_) or _kidneys (_causing renovascular HTN, renal microangiopathy =\> renal failure)
* _Miscarriages_ because patient will have problems wiht _growth and differentiation of trophoblasts, causing there to be no placenta_
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* **Arterial/cardiac thrombi** typically occur at sites of \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
* **Venous thombi** occur at sites of \_\_\_\_\_\_\_\_\_\_.
* **Arterial/cardiac thrombi** typically occur at sites of _turbulence of damage to endothelium_
* **Venous thombi** occur at sites of _stasis_.
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How do thrombi propagate in the blood?
Thrombi are _attached to the vascular surface where the injury occured_.
* **Arterial thrombi** will move **retrograde**
* **Venous thrombi** will move in the **direction of blood flow**
**BOTH TO THE \<3.**
**_The part that propagates is the part that is most likely to break off and embolize._**
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What is the difference between **arterial and venous thrombi?**
**Are they occlusive?**
**Arterial:** common places, what do they consist of, major causes and more prone to embolize what areas?
**Venous**: common places, what do they consist of, features of the clot
* **_Arterial thrombi_** are _frequently occulusive._
* **Most common places (in order**): coronary (MI), cerebral (stroke) or femoral artery.
* **Consist of:** fibrin, platelets, RBC and leukocytes.
* **Major causes include**: atherosclerosis, MI, rheumatic heart disease,
* **More prone to embolize**: _brain_, _kidneys_ and _spleen_ because they have a RICH BS.
* **_Venous thrombi_** are _always occulsive._
* **Most common in:** slow venous circulation of the _LE_
* **Consist of:** red cells and few platelets,making them known as _red/ stasis thrombi._
* **Features**: firm, attached to vessel wall and contain lines of Zahn.
109
**Venous thromb**i are also called what?
**Phlethrombosis.**
110
What is the difference between **superficial venous thrombi** and **deep venous thrombi (DVT)?**
* **Superficial venous thrombi** most often occur in _saphenous vein_ and can cause [_congestion, swelling, pain and tendernes_s] BUT **RARELY embolize.**
* **DVT** occur in large veins of the leg at or above the knee and cause _unilateral swelling, pain, warmth and redness_ below the knee. Dont always occur b/c collateral channels can open
* **More serious because they CAN EMBOLIZE.**
*
111
What are **risk factors for DVT?**
* **1. _Genetics_**
* **2. Inactivity/immnobility**
* **3. Injury:** cause pro-coagulant release, liver makes clotting factors and decrease tPA production.
* **4. Hormone replacement or oral contraceptives**
* **5. _Smoking_**
* **_6. Pregnancy_**
* **7. _Cancer_ (Trousseau syndrome)**
* **_8. Obesity_**
* **_9. Age_**
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1. **Infected endocardial thrombi/vegetation**
2. **Nonbacterial thrombotic endocarditis**
3. **Libman-Sacks endocarditis**
**Vegetations** are a mixture of immune cells and blood clots on heart valves.
1. **Infective endocardial vegetations:** bacteria or fungi can attach to heart valves, causing damage to endothelium and distrubed blood flow =\> form _infective thrombotic masses_
2. **Nonbacterial thrombotic endocarditis:** uninfected vegetations that develop on uninfected valves in a person in a _hypercoagulable state_
3. **Libman-Sacks endocarditis:** sterile errucous(non-bacterial) endocarditis that occurs with lupus
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What are the **4 fates of the thrombus?**
**1. Propogate (grow)** by adding more platelets and fibrin
## Footnote
**2. Embolize**
**3. Go away d/t spontaneous fibrinolysis**
**4. Organize and recanalize**
114
Are newer or older thrombus more likely to go away by **spontenous fibrinolysis?**
**Newer**. Older thrombus are more resistant to lysis.
115
What can be given to a patient to treat to dissolute a thrombus that causes a **embolic stroke?**
**Give exogenous tPA** **within 6 hours of onset.**
116
What happens when a thrombus undergoes **organization and recanilzation?**
* **Older thrombi undergo organization** by _growing endothelial cells_, _smooth cell_s, and _fibroblasts_ to create channels that will allow capillaries to grow and recover lost BF.
* **Recanilization** can convert thrombus =\> smaller mass of CT that incorperates into the wall of the BV, producing a scar
*
117
118
Q:] What happens if a thrombus dislodges?
Becomes an embolus that goes to the lungs (pulmonary embolism).
Originates from a LE DVT and lodges in _pulmonary **arterial** circulation_
119
**Embolism is a detached intravascular solid, liquid or gas carried by the blood from its original point of origin =\> distant site, where it enounters vessesl too small for it to travel through.**
What does it cause?
Most embolisms are what?
* **Partial or complete vessel occulusion, depending on size and location of embolism.**
* **Most are _dislodged thrombi (thromboemolisms)_**
120
**Pulmonary embolism (PE):** PE originate from fragments of DVT -\> larger veins and _____ side of heart -\> lodged within pulmonary _____ circulation
**RIGHT SIDE OF THE HEART**
**PULMONARY ARTERIAL CIRCULATION**
121
\_\_\_\_\_\_\_\_\_\_\_\_\_ is THE most common thromboembolic disease..
**Pulmonary embolism**
122
**The clinical outcome is dependent on the size of the PE.**
Describe the sizes and outcomes.
* **Large PE (saddle embolus)** lodges in primary arterial trunk at the pulmonary artery bifurcation usually instanteously kill you
* If **medium**:
* Travel more peripherally and patients may have SOB.
* _Can cause pulmonary hemorrhage_, _but does **not** cause infarction_ bc the lung is has 2 BS ( pulmonary arteries and bronchial arteries). Bronchial as r enough to prevent infarction
* **Extremely small emboli** emboli can be asymptomic.
123
**What pattern do we see in ppl with PE?**
* **Most (60-80%) PEs are** **small** and overtime will incorperate into the vessel wall and leave behind a **scar**.
* Thus, most are _clinically silent_ because they're small and lung has 2 BS.
* **A pt with 1 PE has an increased risk for more.**
124
* When emboli obstruct more than **60**% of the pulmonary circulation: what happens?
**can cause _sudden death_, _right heart failure,_ or _/;_**
125
What are the **5 types of embolisms?**
**1. Thromboemboli (pulmonary or systemic thromboembolisms)**
**2. Fat/marrow emboli**
**3. Air emboli**
**4. Septic emboli**
**5. Amniotic fluid emboli**
126
What are **systemic thromboemboli?**
**Systemic emboli** arise from the _left heart_ and _lodge into the arterial circulation_, depending on the source and amount of blood flow.
* (80%) arise from **intracardiac mural thrombi**, 2/3 of which are associated with left ventricular wall infarcts and another 1/4 with left atrial dilation and fibrillation.
127
**Systemic thromboemboli** are likely to lodge where
In contrast to venous thromboemboli, they can lodge in many places besides the lung.
In order: **LE (75%), brain, intestines, kidneys, spleen, and UE**
128
What is a **fat/marrow embolism?**
* **Fat emboli** are emboli of the bone marrow (which contains fat)
* _Cause_: Occur in _90% of skeletal muscle injurie_s (fractures o_f long bones or soft tissue_ trauma), often when doing chest compression =\> introduce bone marrow into circulation =\> fat embolism.
* thus, they are **commonly seen post-mortum**
129
What is **fat embolism syndrome?**
* Fat embolism syndrome causes **respiratory distress,** **mental status changes** (irritability, delirium, coma), **anemia** and **thrombocytopenia**.
* Fatal in about 10% of people
130
What is an **air embolism?**
**The introduction of air (iatrogenic) that forms gas bubbles in the circulation, often due to cardiac catheterization.**
Theu _coalesce and form masses that block blood flow and cause distal ischemic injury._
131
**In what cases can we see a gas embolus?**
**Decompression sickness:**
* 1. As patient dives, partial pressure increases, forcing nitrogen to dissolve in the blood.
* 2. As the diver comes up rapidly, nitrogen does not have enough time to leave the blood and will precipitate out of the blood as small gas bubbles and go into tissue.
**Causes**: joint and muscle pain (**_bends_**) and respiratory symptoms (**_chokes_**)
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What is the chronic form of decompression sickness called?
**Caisson disease.**
* Happens to pppl that worked in pressurized vehicles while working on bridges.
* **Persistent bubbles in the skeletal system** leads to **multifocal ischemic necrosis of the bone (femoral head, tibia and humerus).**
133
**Amniotic fluid embolism**
Amnoitic fluid into maternal pulmonary circulation during labor or delivery, causing an **anaphayltic-allergic reaction in mom.**
5th most common cause of maternal mortality, often resulting in _neurological deficits in those that survive._
Mom will have: **_SOB (dyspnea), cyanosis, and shock_,** followed by **n_eurological symptom_**s. If the pt survives, mom can get DIC -\> kill her.
134
What will we find on autopsy in someone who died from amniotic fluid embolism?
* **Squamous cells from kin, hair, fat, mucin from the baby i**n the moms BV
135
**What are septic emboli?**
**and clinical manifestations.**
Blood-borne infective emboli that may occur in endocarditis when vegations on the valve break off and lodge in other wides.
Manifestations:
1. Skin microemboli called **Janeway lesions (purpuric)**
2. Retinal microemboli called **Roth spots**
3. Vascular damage to nails called **splinter hemorrhages.**
136
What is an infarct?
An infarct is an area of ischemic necrosis caused by _occlusion of either the arterial supply or the venous drainage._
137
**Contributing mechanisms to infarction**
Vast majority are d/t
1. **arterial thrombosis**
2. **arterial embolism.**
138
What factors influence infarcts?
**1. Anatomy of vascular supply\* most important**
**2. Rate of occlusion**
**3. Vulnerability of tissue to hypoxia**
139
How can we **classify the morphology of infarcts?**
By _color_ and the _prescence or absence of infection:_
## Footnote
**1. Red (hemorrhagic) infarcts**
**2. White (anemic) infarcts**
140
What are **red (hemorrhagic) infarcts?**
Red (hemorrhagic) infarcts are **rich in RBC** and most commonly occur in **LE.**
Occur in:
1. **Venous occlusions,** which causes **stasis** of blood.
2. **Loose tissues like lungs**
3. **Tissues with 2 BS** (lungs and SI)
4. **Sites that were previously occluded** and necrototized when flow is reestablished.
141
What are **white (anemic) infarcts?**
White (anemic) infarcts are **platelet rich** and caused by **_arterial occlusions in compact (solid) tissue that have one BS d/t high shear stress._**
1. solid organs that have 1 BS: [heart, spleen and kidneys]
2. _arthersclerosis of the coronary and cerebral arteries \*\*\*\*\*\*_
142
Organs more dependent on one vessel-\> ____ infarction
Organs with 2 BS -\> ____ infarction
* **Organs more dependent on one vesse**l-\> white infarction
* **Organs with 2 BS** -\> red infarction
143
* Factors that influence the development of an infarct: Rate of occlusion
* Slower occlusions are more likely not going to cause tissue damage since collateral supply will have time to adequately compensate for the occlusion.
144
* Factors that influence the development of an infarct: Tissue vulnerability to hypoxia
* **Neurons** die to hypoxia in 3-4 min.
* **Myocardial cells** die to hypoxia die in 20-30 min.
* **Fibroblasts** within the myocardium take several hours to die of hypoxia
* Never see liver infarcts
Thus, **brain** is most vulnerable
145
**All infarcts** tend to be \_\_\_\_\_\_-shaped: \_\_\_\_\_\_\_.
**wedge shaped: the occluded vessel is at the apex and organ periphery is the base.**
146
What is the dominant histologic feature of infarction?
What is the exception?
* Display _ischemic coagulative necrosis_ unless the person died before the histology took place (it takes 4-12 hours).
* Followed by inflammation along margins that lasts hours -\> days
* THEN, folowed by reparative response (days to weeks) initiated in the preserved region to form a scar.
* **Exception: brain undergoes liquifactive necrosis.**
147
What is shock?
* Shock: **systemic hypoperfusion and cellular hypoxia** d/t from reduction in CO or hypotension
* Injury is only reversiblr at the begining.
148
**What are the 3 types of shock?**
1. **Cardiogenic shock**
2. **Hypovolemic shock**
3. **Septic shock (shock associated with systemic inflammation)**
149
How does cardiogenic shock occur and what causes it?
* **Mechanism**: _Obstruction of flow_ or _failure of myocardial pump_ d/t intrinsic myocardial damage, extrensic compression =\> decrease in CO.
* **Causes**: MI, ventricular rupture, ventricular arrhythmias, cardiac tamponade, PE
150
How does hypovolemic shock occur and what causes it?
* **Mechanism**: Low blood volume causes low CO.
* **Causes**: massive hemorrhage or fluid loss from severe burns, trauma, V/D.
*
151
How does **septic shock** occur and what causes it?
Septic shock is d/t **microbial infection/superantigens/burn/trauma/pancreatitis** that causes **systemic inflammation** =\>
* release of innate/adaptive inflammatory mediators =\> _vasodilation_ and venous _blood pooling._
* =\> can lead to:
* tissue hypoperfusion,
* decrease O2 in tissue
* metabolic derangements
* **=\> organ dysf/failure/death**
152
* **Septic shoc**k is most commonly triggered by (decreasing order): \_\_\_\_\_\_, _______ and \_\_\_\_\_\_
1. **gram + bacteria**
2. **gram - bacteria**
3. **fungi**
153
* **Pathogenesis of Septic Shock: How do we get from pathogens to decreases tissue oxygenation?**
* Describe the steps.
* 1. Inflammatory responses
* A. PAMPS on pathogenic bacteria and fungi interact with TLRs of the innate immune system.
* B. Once activated innate immune system releases **TNF, IL-1, IFN-γ, IL-12, IL-18, and HMGB1.**
* Release ROS, lipid mediators, prostaglandins, and PAF.
* C. Complement system is also activated directly and through proteolytic activity of plasmin =\> C3a/C5a, C3b=\> pro-inflammatory state.
* D. Hyperinflammatory state cause IL-10 and sTNF release and apoptosis =\> cause immunosupresion, which is counter-regulatory.
* Thus, septic patients may switch between hyperinflammatory and immunosuppressed states.
* 2. Endothelial activation
* A. Inflamm cytokines loosen endothelial tight jcts =\> increase permeability
* =\> Leads to vasc leakage of protein- rich edema, causing hypovolemia
* B. Endothelium releases NO =\> Vasodilation =\> decreased bp =\> hypotension
* 3. Procoagulation
* Increase factor 12 and TF and decreased antithrombin and protein C =\> decrease fibrinolysis (by increasing plasminogen activator inhibitor-1) =\> tissue begins to thrombose.
* This can cause DIC
* 4. Metabolic abnormalities such as insulin resistance and hyperglycemia occur
* **5. Hypotension, hypovolemia and thrombosis alllll cause a DECREASE in ORGAN OXYGENATION =\> end-stage multiorgan failure**
*
154
What exactly causes the **end-stage multi-organ dysfunction?**
* **Systemic hypotension, lots of edema, and small vessel thrombosis:** decrease delivery of O2 and perfusion of tissues.
* **Cytokines and secondary mediators=\>** decrease contraction of heart =\> reduce CO.
Lead to mutilple organ failure (usually **kidneys, liver and lungs**) =\> death.
155
25.Describe the clinical consequences/prognosis of shock.
**The prognosis varies with the origin of shock and its duration**
* Hypovolemic shock and cardiogenic:
* 1. Hypotension
* 2. weak rapid pulse
* 3. tachypnea
* 4. cool, clammy, cyanotic skin.
* Septic shock:
* 1. Skin may initially be warm and flushed d/t vasodilation.
* 2. Then, shock causes cardiac, cerebral and pulmonary dysftion =\> disturb electrolytes and metabolic acidosis
* Second phase: renal insufficieny =\> decrease urine output
156
**What cell and tissue changes do we see in those with cardiogenic or hypovolemic shock?**
Changes caused by hypoxia: seen mostly in the _brain_, _heart_, _lungs_, _kidneys_, _adrenals_ and _GI tract._
* Adrenal: inactive cells become active and use up lipid stores by converting them to steroids
* Kidenys: acute tubular necrosis.
* Lungs: sepsis can cause diffuse alveolar dmage (shock lung)
* Microthrombi in organs listed above.
* Serosal surface and skin: petechail hemorrhages.
All of these changes, except to ones in brain and heart can go back to normal if the patient survives.
