Balance between EC anti- and prothrombotic activities

determines whether thrombus formation, propagation,

or dissolution occurs.
ANTITHROMBOTIC PROTHROMBOTIC
1.) Blocks platelet access 1.) Von Willebrand Factor
2.) PGI2 & NO *adhesion
3.) ADP 2.) Tissue Factor
4.) TFPI *secondary hemostasis
3.) Plasminogen Activator
Inhibitors (PAI)
ANTITHROMBOTIC PROPERTIES
ENDOTHELIAL ANTI-PLATELET EFFECTS
HISTOPATHOLOGY Physical barrier/ Intact endothelium
o Prevent platelet contact w/ ECM
HEMOSTASIS, THROMBOSIS, EMBOLISM
NON ACTIVATED PLATELETS ACTIVATED PLATELETS
HEMOSTASIS Do not adhere to endothelial Adheres
cells But inhibited by:
Transient reflex neurogenic arteriolar vasoconstriction
augmented by endothelin. PGI2 & NO
Platelet adhesion and activation *vasodilator and platelet
Activation of coagulation cascade aggregation inhibitors
Activation of counter-regulatory mechanism ENDOTHELIAL ANTICOAGULANT EFFECTS
FOUR COMPONENTS: Mediated by membrane-associated, heparin-like
1. Vascular Wall (endothelium) molecules and thrombomodulin and anti-thrombin III.
2. Platelet Heparin-like molecules
3. Coagulation cascade o Act indirectly
4. Fibrinolytic system o enhance the inactivation/inhibits thrombin and
several other coagulation factors by the plasma
protein antithrombin III
o Thrombomodulin binds to thrombin
*converts it from a procoagulant into an
anticoagulant via its ability to activate protein C, w/c
inhibits clotting by inactivating factor Va and VIIIa
Heparan Sulfate Proteoglycans/HSPG/Heparin
o Natural anticoagulant
o No function in Invivo
o Binds w/ Antithrombin III (circulating plasma protein) to be
active or to have a function as an anticoagulant; and it’s fxn is
to prevent thrombin action
Thrombin (IIa)
o enzyme that came from Prothrombin (Factor II)
o Primary action: conversion of fibrinogen to fibrin.
HEMOSTASIS THROMBOSIS o Thrombin Receptor: Protease Activated Receptor (PAR)
Normal, physiologic process Pathologic state o Inhibitor: Heparin
maintain blood in a fluid, clot-free Inappropriate activation of o Activator: enzymatic cleavage of two sites on prothrombin by
state w/in normal vessels while hemostatic mechanisms in activated Factor X
inducing a rapid, localized uninjured vessels or thrombotic o Antithrombotic
hemostatic plug at sites of occlusion after relatively minor o Activated thrombin:
vascular injury. injury. ACTIVATES INHIBITS
Depend on 3 components: FACTOR V, VIII, XIII & IX Factors IX, X, XI, & XII
(1)endothelium Protein C Kallikrein and Plasmin
(2)platelets Induce clotting
(3)coagulation cascade Thrombomodulin
ENDOTHELIUM o will bind to the circulating thrombin, forming a
Endothelial cells – regulate opposing aspects of thrombomodulin-thrombin complex. It will then facilitate the
activation of Protein C into active protein C. Cofactor involved is
hemostasis.
Protein S.
Can also be activated by: *Is protein C and Protein S a clotting factor?
o Infectious agents - No. They are plasma proteins just like the antithrombin and
o Hemodynamic forces located in the endothelium.
o Plasma mediators o Once Protein C is activated, it will inhibit active V and VIII. It will
o Cytokines inhibit platelet aggregation and Factor I activation.
NORMALLY EXHIBIT: AFTER INJURY/ACTIVATION *Factor V and VIII are sometimes called the Labile clotting factors
(1)antiplatelet (1)procoagulant function Tissue Factor Pathway Inhibitor (TFPI)
1

(2)anticoagulant o Cell surface protein that directly inhibits tissue factor (Factor VIIa
and Factor Xa)
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(3)fibrinolytic properties
 ENDOTHELIAL FIBRINOLYTIC EFFECTS *once there is injury to the tissue lining the endothelium, it will produce
Synthesize tissue type plasminogen activation (t-PA) cytokines that will induce inflammatory processes:
promoting fibrinolytic activity. o TNF – tissue necrosis factor
o IL-1 – interleukin 1
t-PA – a protease that cleaves plasminogen to form
plasmin (cleaves fibrin to degrade thrombi) PLATELETS
When circulating are membrane-bound smooth dse.
They contain 2 specific types of granules:
-GRANULES DENSE GRANULES
Contain fibrinogen, fibronectin, Contain adenine nucleotides (ADP
factors V& VIII, platelet factor 4, and ATP), ionized calcium,
platelet-derived growth factor histamine, serotonin and
(PDGF), and transforming growth epinephrine
factor β (TGF-B)
vWF; adhesive proteins; growth Release potent aggregating
factors; coagulation factors agents (ADP, ATP, histamine,
PROTHROMBIC PROPERTIES serotonin, epinephrine – induces
Normal endothelium produces vWF facilitates adhesion vasoconstriction)
of platelets to ECM (not synthesized in response to PVTBF CHAPS
injury). Calcium – required in coagulation
Tissue factor secretion by endothelium is induced by cascade.
cytokines (e.g. TNF, IL-1) or bacterial endotoxin ADP – activation of platelet
o Tissue factor activates the extrinsic clotting aggregation.
pathway
Endothelial cells secrete plasminogen activator inhibitors
(PAIs) w/c depress fibrinolysis thus promoting
thrombosis.
PLATELET EFFECTS
Endothelial injury allows platelets to contact the
underlying extracellular matrix
Subsequent adhesion:
Platelets + vWF
PROCOAGULANT EFFECTS
In response to cytokines (e.g. tumor necrosis factor (TNF) Plasminogen Activator Inhibitor (PAIs) – inhibits activation of
or interleukin-1 (IL-1) or bacterial endotoxin, endothelial plasminogen. No plasminogen activation → no plasmin → no lysis of
cells synthesize tissue factor, the major activator of the clot → thrombotic
extrinsic clotting cascade PLATELET ACTIVATION
Activated endothelial cells augment the catalytic On contact w/ ECM, platelets undergo:
function of activated coagulation factors IXa and Xa. o Adhesion and shape change
ANTIFIBRINOLYTIC EFFECTS o Secretion (release reaction)
Endothelial cells secrete inhibitors of plasminogen o Aggregation
activator (PAIs) w/c limit fibrinolysis and tend to favor PLATELETS
thrombosis. After vascular injury, platelets encounter ECM
INHIBIT THROMBOSIS (ANTITHROMBOTIC) constituents (collagen, proteoglycans, fibronectin, and
THROMBIN will bind to Thrombomodulin, activating Protein other adhesive glycoproteins), which are normally
C w/ cofactor Protein S w/c will inhibit factor Va
sequestered beneath an intact endothelium.
and Factor VIIa
Then, platelets undergo activation involving adhesion
HEPARIN will bind to plasma protein antithrombin IIIa will
inhibit factors X, VIII, IX and shape change, secretion (release reaction), and
PGI₂ & NO Inhibits platelet aggregation aggregation.
TfPI Inhibits tissue factor and factor VII PLATELET ADHESION Platelets + vWF + GPIb-IX / Collagen
*tissue factor/Factor III and factor VII – extrinsic pathway factors Receptor: GP1b-IX
FAVOR THORMBIN (PROTHROMBOTIC) Pandikit: vWF
COLLAGEN Once exposed, it will activate the platelets w/c (Source of vWF: endothelial cells, weibel
will undergo ASA (adhesion, secretion and palade bodies, megakaryocytes)
aggregation) and will form the primary PLATELET SECRETION *Both granules are released & explode soon
hemostatic plug. Exposed collagen will also after adhesion.
activate the EXTRINSIC PATHWAY *Calcium and ADP: potent mediators of
TISSUE FACTOR Release will activate the extrinsic, intrinsic, coagulation and platelet aggregation.
common pathway with fibrin as an end product - – PVTBF (growth factors)
VON Sources: Dense – CHAPS (calcium, ATP, ADP)
WILLEBRAND o Weibel pallade bodies PLATELET *ADP and TXA2 stimulate further platelet
o Platelets (α granules) AGGREGATION adhesion
o Factor VIII (vWF attached to Factor VIII will *This sets up an autocatalytic reaction
2

stabilized Factor VIII) leading to an enlarge platelet mass the

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primary hemostasis plug

 *This is a “reversible” collection of
platelets. INTRINSIC PATHWAY
Receptor: GPIIb-IIIa EXTRINSIC PATHWAY
Pandikit/intracellular bridge: Fibrinogen
COMMON PATHWAY
Platelets→Aggregation: GPVa
*intrinsic + extrinsic → common pathway → secondary hemostatic
plug (thrombus)
CLOTING FACTORS
FACTOR I Fibrinogen Forms clot (fibrin)
FACTOR II Prothrombin
FACTOR III Tissue thromboplastin or Co-factor of VIIa
tissue factor or tissue juice
FACTOR IV Ionized calcium (Ca2+) Required for
coagulation factors
to bind to
phospholipid
FACTOR V Labile Factor or Co-factor of X
Proaccelerin
FACTOR VI Antihemophilic factor
FACTOR VII Stable factor or Activates IX, X
Proconvertin
FACTOR VIII Antihemophilic Factor A, Co-factor of IX
Antihemophilic Globulin (Hemophilia A)
FACTOR IX Plasma Thromboplastin Activates X
Component, Christmas (Hemophilia B)
factor, Antihemophilic
Factor B
FACTOR X Stuart-Power Factor Activates II: forms
prothrombinase
complex w/ factor V
FACTOR XI Plasma Thromboplastin Activates IX
Antecedent, Hemophilia C,
Rosenthal syndrome
FACTOR XII Hageman factor Activates factor XI,
VII, and prekallikrein
FACTOR XIII Fibrin-stabilizing factor, Cross-links fibrin
FROM CELL MEMBRANE PHOSPHOLIPIDS (ARACHIDONIC ACID) Laki-Lorand Factor
*effect of aspirin Prekallikrein Fletcher factor Activates XII; cleaves
LIPOXYGENASE CYCLOOXYGENASE HMWK
Inhibited Promoted High-molecular Fitzgerald factor Supports reciprocal
Leukotrienes TXA2 PGI2/Prostacyclin weight activation of XII, XI,
kininogen and prekallikrein
Promotes platelet Inhibits platelet
(HMWK)
aggregation → thrombosis aggregation
Def: bleeding Def: thrombosis COAGULATION CASCADE
vasoconstriction vasodilation Thrombin – most important coagulation factor
sequence of inactive proenzymes are converted into
activated enzymes, culminating in the generation of
insoluble fibrin from the soluble plasma protein
fibrinogen.
Conversion of Pro-factors to Activated Factors
Culminating in the formation of Thrombin
Thrombin converts fibrinogen → fibrin
Fibrin is critical for hemostasis
Occurs on a “phospholipid substrate”
o Such as on the surface of activated platelets
o Held together by calcium ions
This helps to localize the thrombus
o To sites of platelet aggregation
3
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Schematic illustration of the conversion of factor X to factor Xa via the ENDOTHELIAL INJURY
extrinsic pathway, which in turn converts factor II (prothrombin) to Sources include:
factor IIa (thrombin). The initial reaction complex consists of a o Severe atherosclerosis
proteolytic enzyme (factor VIIa), a substrate (factor X), and a reaction
o Hypertension
accelerator (tissue factor), all assembled on a platelet phospholipid
surface. Calcium ions hold the assembled components together and are o Toxic products (cigarettes, homocysteine Etc)
essential for the reaction. Activated factor Xa becomes the protease for ABNORMAL BLOOD FLOW
the second adjacent complex in the coagulation cascade, converting TURBULENCE STASIS
prothrombin substrate (II) to thrombin (IIa) using factor Va as the Irregular flow of blood, w/c makes No laminar nor axial flow; cells are
reaction accelerator. the cells stick or cause injury to stagnant in the vessels and the
EXTRINSIC PATHWAY the BV wall that will make it prone nearer it is to the vessel wall the
to thrombosis more it is possible to cause injury
Requires exogenous trigger (originally provided by tissue
Swirls, Eddies and ↑ Pressure are
extracts)
injurious
Most physiologically relevant pathway for coagulation Arterial and Cardiac thrombosis Venous thrombosis
occurring when vascular damage has occurred causing cardiac injury or
Prothrombin Time (PT) – Factor VII, X, II, V and fibrinogen dysfunction
o (Tissue factor + Phospholipids) + Citrated Plasma These change occur in arteries and the heart
o Coagulation is initiated by the addition of exogenous o Atherosclerosis, aneurysms, MI, Cardiac Valve lesions
calcium and the time for a fibrin clot to form is o Hyperviscosity Syndromes e.g. Sickle Cell Anemia,
recorded. Polycythemia
INTRINSIC PATHWAY More commonly a problem on the venous side leading
Requires exposure to Factor XII (Hageman Factor) to to venous thrombosis
thrombogenic surfaces Can occur in the heart given atrial fibrillation or
Activator: Collagen infarction.
Main Activator: Kallikrein Turbulence and Stasis:
Partial Thromboplastin Time (PTT) – screens for the fxn o Promote endothelial activation, enhancing
of the proteins (Factor TENET) procoagulant acitivity, leukocyte adhesion etc.
o Clotting is initiated through the addition of (-) o Disrupt normal laminar flow and bring platelets
particles in contact w/ endothelium
THROMBOSIS o Prevent dilution of Activated Clotting Factors
Retard the inflow of clotting Factor inhibitors and permit
THROMBUS – blood clot inside a blood vessel
thrombi build-up
POST MORTEM BLOOD CLOT THROMBUS
Promotes endothelial cell activation
No activation of endothelial Will activate endothelial system
ANEURYSM – weakened medial part of the layer of the blood vessel →
system; no injury in the
stagnant → will not pulsate normally → changes in blood flow →
endothelium
endothelial injury
Will not activate platelets Will activate platelets
MI – part of myocardium is not contracting → stasis → thrombosis
Not attached Attached to the blood vessel wall
CARDIAC VALVE LESIONS – vegetations (thrombosis of the heart valves)
Has 2 layers: Lines of Zahn – composed of o Septic – infected w/ bacteria; may be secondary to subendocardial
Top: Plasma platelets, fibrin, RBCs; seen in endocarditis
Bottom: RBC clot & Fibrin clot both arterial and venous o Aseptic/Verrucous/Marantic – non-infective; secondary to
thrombus but more evident in autoimmune condition like Rheumatic Heart disease from RF due
venous site (coz yung flow is mas to recurrent sore throat (caused by β hemolytic streptococci group
mabilis sa arterial kaya rare na D) stimulating your immune system to make antibodies against the
makagawa ng lines of Zahn) M protein found in the walls of the Group D Strep; autoantibodies
Both involved in the coagulation system are formed in the blood stream, cross reacting w. another M
PF3 – will stabilize activated platelets held on by calcium; phospholipid protein located in the heart; immune complex will deposit in the
+ calcium + factors from intrinsic pathway – intrinsic tenase will activate heart activating the complement system (MAC, Opsonin,
Factor X. Anaphylatoxin)
Extrinsic sense
Prothrombinase – tissue thromboplastin w/c will activate prothrombin HYPERCOAGULABILITY
→ thrombin → finbrinogen → fibrin →clot Any alterations of the coagulation pathways that
PATHOGENESIS – VIRCHOW’S TRIAD predispose to thrombosis
Endothelial injury Primary (Genetic) or Secondary (Acquired) disorders
Stasis or turbulence of blood flow HYPERCOAGULABILITY MUTATION OF FACTOR V GENE
Blood hypercoagulability o Factor V Leiden Mutation is the most common
inherited cause of hypercoagulability
o Mutant factor V is resistant to the anti-coagulant
effect of activated protein C
- thus there is a functional deficiency of Protein C
INHERITED LACK OF OTHER ANTICOAGULANTS
o Lack of Protein S, Protein C and Antithrombin III
o Px will present w/ Venous thrombosis and recurrent
thromboembolism in adolescence and early adulthood
4

o Factor V Leiden Mutation is most common

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OTHER ASSOCIATIONS:
 o Smoking, obesity, oral contraceptives (BCP) 6.) Sickle cell anemia
o Lupus “anticoagulant” w/ lupus erythematosus 7.) Smoking
(arterial and venous thrombosis) MORPHOLOGY OF THROMBI
- Called an anticoagulant because it interferes w/ a thrombi develop in the cardiovascular system
coagulation test, artificially prolonging it thus, bleeding into the peritoneal area
- But it is not an anticoagulant. It’s a procoagulant. o Ex: forms a blood clot – not a thrombus
Blood is viscous (malapot) – that makes an abnormal blood flow and Clot Thrombus
there’s a tendency that the cells will get in contact w/ the endothelium Platelets not involved Platelets involved
w/c may injure it because of the sluggish flow.
Occurs outside vessel (test tube, Occur only inside vessel
VIRCHROW’S TRIAD SUMMARY hematoma) or inside (post
ENDOTHELIAL INJURY dominant and can independently mortem)
cause thrombosis Red Red (venous), Pale (arterial)
ALTERATIONS IN • Disrupt laminar flow and bring platelets Gelatinous Firm
NORMAL BLOOD FLOW into contact with Not attached to the vessel wall Attached to the vessel wall
the endothelium. Lines of Zahn
• Prevent dilution of activated clotting o Alternating pale layers of platelets & fibrin w/
factors by flowing blood. darker layer of RBC’s.
• Retard the inflow of clotting inhibitors.
o Imply formation in areas of active blood flow
• Promote endothelial cell activation.
HYPERCOAGULABILITY loosely defined as any alteration such as in the heart, aorta or larger arteries
of the coagulation pathways that predisposes o Venous thrombi form in a more sluggish flow
to thrombosis. zone and often lack lines of Zahn
It contributes less frequently to thrombosis
MURAL THROMBI
but is critical in
certain conditions Thrombi occurring in heart or aorta

Mutation of Factor V gene – Factor V Leiden mutation

o Leads to functional deficiency of protein C
o Patient will have venous thrombosis and recurrent
thromboembolism
Systemic Lupus Erythromatosus
o Prolonged coagulation tests; false prolongation of the
clotting factor tests
o False (+) serologic test syphilis; RPR & VDRL will be false
(+) ARTERIAL THROMBI
WHICH AMONG THE 3 IS THE MOST IMPORTANT? ENDOTHELIAL INJURY Arterial thrombi are usually occlusive
ATHEROSCLEROTIC PLAQUE Usually begin at a site of endothelial injury and grow
o Not a thrombus but its complication may lead to along flow of blood
thrombosis; located in the endothelial lining/intimal lining in Typically are firmly adherent to the injured arterial wall
the fat deposits (atherosclerotic plaque)
o Bigger plaque = nababara yung dugo = blood flow will
decrease = barado na totally → ischemia → infarction → CLINICAL SETTINGS FOR CARDIAC/ARTERIAL THROMBUS
organ distal to the block will die FORMATION
o COMPLICATIONS: Myocardial infarction (MI)
1.) Calcify Rheumatic heart disease
2.) Ulcerate
Atherosclerosis
3.) Thrombosis
4.) Aneurysm ARTERIAL/CARDIAC THROMBI VENOUS THROMBI
5.) Hemorrhage Turbulence or endothelial injury Site of stasis
Retrograde from point of Extend in the direction of blood
CONDITIONS ASSOCIATED W/ AN INCREASED RISK OF THROMBOSIS
attachment flow (propagate towards the
PRIMARY (Genetic)
heart)
o Mutations in factor V
o Antithrombin III deficiency VENOUS
o Protein C or S deficiency Venous thrombi are almost always occlusive
o Fibrinolysis defects o 85-90% of venous thrombi form in lower
SECONDARY (Acquired)
extremities
o High risk for thrombosis
1.) Prolonged bed rest or immobilization
Superficial veins of the lower extremities
2.) Myocardial infarction o Cause pain, swelling – rarely embolize
3.) Tissue damage (surgery, fracture, burns) o Associated w/ varicosities
4.) Cancer - Varicose Veins – abnormally dilated,
5.) Prosthetic cardiac valves tortous veins
6.) DIC o ↑ risk of infections
7.) Lupus anticoagulant o ↑ risk of varicose ulcers
o Low risk of thrombosis
Thrombin in deep veins (Popliteal, femoral, Iliac Veins)
1.) Atrial fibrillation
2.) Cardiomyopathy
more likely to embolize
About 50% are asymptomatic (formation of collaterals)
5

3.) Nephrotic syndrome

May produce edema, pain and tenderness
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4.) Hyperestrogenic states

5.) Oral contraceptive use
 CLINICAL SETTINGS FOR VENOUS THROMBUS FORMATION 99% are dislodges thrombus
Cardiac failure (CHF); Trauma; Surgery; Burns Potential consequence: ischemic necrosis (infarction)
3rd term pregnancy and postpartum o Repeat potential. Not always, depends on the
Cancer organ
o Migratory thrombophlebitis (Trousseau’s Rarely: bullets, fat, air, atherosclerotic fragments, tumor
syndrome) fragments, BM
Bed rest Potential consequences:
Immobilization o Ishemic necrosis (infarction)
CLINICAL CORRELATION: o Though pulmonary emboli are common and
o Obstruction important, secondary pulmonary infarction is
o Embolization not common
o Lung is protected by a dual blood supply
VASCULAR THROMBI
o The brain is not so protected and gets infarcts
Infective endocarditis
(stroke) LIQUEFACTIVE NECROSIS
Non-bacterial thrombotic endocarditis
Verrucous endocarditis (Libman-sacks) PULMONARY THROMBOEMBOLISM
Lupus related Generally originate from the deep leg veins
Usually pass through the right heart into pulmonary
FATE OF THROMBUS
vasculature
Propagation and obstruction
PULMONARY EMBOLUS:
Embolization
o “paradoxical embolism” – an embolus pass
Dissolution – nothing left
through an interarterial or intraventricular
Organization and recanalization
defect to gain access to the system circulation
Propagation o Most pulmonary emboli (60-80%) are clinically
Embolization Thrombi dislodge and travel to other sites silent because of small size
Dissolution Dissolution by fibrinolytic activity >60% pulmonary AA obstruction usually leads to sudden
Organization and Ingrowth of endothelial cells, smooth muscle
death
recanalization cells, and fibroblasts to create vascular
channels, or incorporate the thrombus into the
o Right heart failure
vessel wall Embolic obstruction of medium-sized arteries may result
Mycotic aneurysm Rarely, microbial seeding of a thrombus leads in hemorrhage w/o infarction because of intact bronchial
to a mycotic aneurysm circulation
If bronchial circulation is compromised like in left heart
DISSOLUTION OF THROMBI
failure:
Recent thrombi can undergo total lysis
o Then an infarct can occur
After the first 2-3hr, thrombi won’t undergo lysis
o Remember, infarction depends on the organ
o Thus the use of TPa is only effective in the first
Multiple pulmonary emboli over time may cause
1-3 hours
pulmonary hypertension and right heart failure
ORGANIZATION/RECARNALIZATION Initial PE increases the risk for more PE
Granulation tissue followed by capillary channel May occlude main pulmonary artery, across the
formation or bifurcation (saddle embolus) or pass into the smaller
May heal so totally as to leave only a small fibrous branching arterioles; multiple emboli may occur
“lump” as evidence of a previous thrombus

SYSTEMIC THROMBOEMBOLISM
EMBOLISM
Emboli traveling w/in the arterial circulation
An embolus is a detached intravascular solid, liquid or
80% arise from intracardiac mural thrombi
gaseous mass that is carried by the blood to a site distant
from its point of origin FAT EMBOLISM SYNDROME
Intravascular foreign material carried in the bloodstream Microscopic fat globules derived from long bone
to a point distant from its origin fractures (fatty marrow), or rarely from soft tissue,
Refers to any intravascular solid, liquid, or gaseous mass trauma and burns
carried by blood flow to a site distant from its origin. 10% of cases are fatal
Most (i.e., 99%) arise from thrombi, hence the term Pulmonary insufficiency
thromboembolism. Rare forms include fat droplets, gas Neurologic symptoms
bubbles, atherosclerotic debris (atheroemboli), tumor Anemia
fragments, bone marrow, or foreign bodies (e.g., Thrombocytopenia
6

bullets). Emboli lodge in vessels too small to permit

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further passage, resulting in partial or complete vascular

occlusion and ischemic necrosis (infarction).
 AIR EMBOLISM
Gas bubbles w/in the circulation can obstruct vascular
flow to cause distal ischemic injury
o Chest wall injury
o Sudden atmospheric pressure changes
(decompression sickness e.g. Divers)
AMNIOTIC FLUID EMBOLISM
Torn placental membrane – amniotic fluid release
Rupture of uterine veins
Infusion of amniotic fluid into maternal venous
circulation
Lungs show squamous cells, lanugo hair, fat from venix
caseosa
Pulmonary edema, diffuse alveolar damage
DIC

7
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