Hemodynamic

Disorders - 1

Dirar Medhanie, MD, Pathologist

 Outlines
o Edema
o Hyperemia and congestion
o Hemorrhage
o Hemostasis and thrombosis
o Embolism
o Infarction
o Shock
2
 Edema
60 % of lean body weight is water,
o 2/3 is intracellular
o 1/3 is extracellular compartments,
mostly as interstitial fluid
Only 5% of total body water is blood plasma

3
 Edema
 Edema =increased fluid in the interstitial tissue spaces
and body cavities.
 Fluid collections in different body cavities:
o Hydrothorax
o Hydroperitoneium
o Hydropericardium
o Anasarca is a sever and generalized edema with
pronounced subcutaneous tissue swelling

4
 Mechanisms for edema formations
1.increased hydrostatic pressure
Causes
o Localized increases in intravascular pressure can result
from impaired venous return
Eg. lower extremity DVT
o Generalized increases in venous pressure
Eg. CHF
5
2.reduced oncotic pressure
oAlbumin is the serum protein most responsible
for maintaining intravascular colloid osmotic
pressure.
oDeficiency of albumin results in decreased
osmotic pressure
6
 Causes
oNephrotic syndrome
oProtein malnutrition
oDiffuse liver damage(liver cirrhosis)
oProtein loosing enteropathy

7
 3.lymphatic obstruction
oImpaired lymphatic drainage and consequent
lymphedema

oCauses: inflammatory, neoplastic conditions

8
Edema is most commonly encountered in
o Subcutaneous tissues
o Lungs, and
o Brain

9
Subcutaneous edema
o Can be diffuse or more prominent in regions with
high hydrostatic pressure
o Gravity dependent distributions called dependent
edema
o Finger pressure over significantly edematous
subcutaneous tissue displaces the interstitial fluid
and leaves a finger-shaped depression called
pitting edema
10
• Subcutaneous edema of the eye-lid is called
periorbital edema

11
 2.Pulmonary edema
o Most commonly seen in LV failure
o Other causes: ARDS, pulmonary infections,
hypersensitivity reactions
o The lungs become 2-3x their normal weight

12
 3.Brain edema
o Can be localized(abscess or neoplasm) or
generalized(encephalitis)
o In generalized edema-the brain is grossly
swollen with narrowed sulci and distended
gyri, showing signs of flattening against the
underlying skull
13
 Hyperemia and congestion
o The terms Hyperemia and congestion both
indicate a local increased volume of blood in a
particular tissue
o Hyperemia is an active process resulting from
augmented blood flow due to arteriolar dilation
o The affected tissue is redder than normal
because of engorgement with oxygenated blood.
14
o Congestion is a passive process resulting from
impaired venous return out of a tissue
o It may occur systematically or locally. The tissue
has a blue-red color(cyanosis)
o Congestion of capillary beds is closely related to
the development of edema, so that congestion
and edema commonly occur together

15
o In long-standing congestion, called chronic passive
congestion cell death can occur due to chronic hypoxia
o Capillary rupture at such sites of chronic congestion can
also cause:
 Small foci of hemorrhage
 Phagocytosis and catabolism of the erythrocyte debris can
result in accumulations of hemosiderin-laden macrophages

16
 Hemorrhage
o Is extravasation of blood from vessels in to the
extravascular space
o An increased tendency to hemorrhage(usually with
insignificant injury) ocurs in a wide variety of clinical
disorders collectively called hemorrhagic diatheses.
o Can be external or can be confined with in a tissue; any
accumulation is referred to as a hematoma.

17
o Minute (1-2 mm) hemorrhages in to the skin,
mucous membranes, or serosal surfaces are
called petechiae.
o Slightly large(3-5 mm) hemorrhages are called
purpura.
o Larger(1-2cm)subcutaneous hematomas(bruises)
are called ecchymosis.
18
Large accumulations of blood in one or
another of the body cavities are called:
o Hemothorax
o Hemopericardium
o Hemoperitoneum
o Hemarthrosis
19
The clinical significance of hemorrhage
depends on the
o Volume and rate of blood loss
o Site of bleeding

20
 Hemostasis and thrombosis
Normal hemostasis is the result of a set of well
regulated processes that accomplish two
important functions:
o Maintain blood in a fluid, clot-free state in normal
vessel
o Induces a rapid and localized hemostatic plug at
the of vascular injury
21
Thrombosis is inappropriate activation of normal
hemostatic process such as formation of blood
clot(thrombus) in an uninjured vasculature or
after minor injury
Both hemostasis and thrombosis are regulated
by:
o Vascular wall
o Platelets
o Coagulation cascades 22
 Thrombosis
Three primary factors predispose to thrombus
formation- Virchow triads:
o Endothelial injury
o Stasis or turbulence of blood
o Hypercoagulability

23
24
 Endothelial injury
It is particularly important for thrombus formation
occuring in heart or in arterial circulation, where the
normally high flow rates might otherwise hamper clotting
by preventing platelet adhesion or diluting coagulation
factors.
Physical loss of endothelium leads to:
o Exposure of subendothelial ECM
o Adhesion of platelets
o Release of tissue factor
25
 Stasis or turbulence of blood
oTurbulence results in arterial and cardiac
thrombosis by causing endothelial injury or
dysfunction
oStasis causes thrombosis in venous thrombosis,
cardiac chambers, and arterial aneurysms
Eg. Aortic or arterial aneurysm-stasis
•Myocardial infarction-stasis
•Mitral valve stenosis-stasis
•Hyperviscosity syndrome (polycythemia)

26
 Hypercoagulability
Is defined as any alteration of the coagulation
pathways that predispose to thrombosis
The cause can be:
oPrimary(genetic) or,
oSecondary (acquired)
27
 Secondary causes
 High risk
oImmobilization
oMyocardial infarction
oAtrial fibrillation
oTissue damage (surgery, fracture, burn,…)
oAntiphospholipid syndrome
oProsthetic cardiac valves
28
 Low risk
o Cardiomyopathy
o Nephrotic syndrome
o Hyperesrogenic state
o OCP
o Smoking
29
Morphology of thrombi
o They are of variable size and shape depending
on their origin and cause
o Cardiac and arterial thrombi are grey-red and
have gross and microscopic apparent
laminations called lines of zahn
30
o This is produced by an alternating pale layers
containing platelets admixed with some fibrin
and a darker layer containing red cells
o Venous thrombosis forms red-blue
appearance with the thrombus consisting of
enmeshed red cells among sparse fibrin
31
Most common sites of arterial thrombi in
descending order are:
o Coronary artery
o Cerebral artery
o Temporal artery
>90% of venous thrombi occur in the lower
extremities
32
Thrombi may also form on heart valves
• In infective endocarditis, bacterial or fungal
infections form large infected thrombotic masses
called vegetations
• Causing underlying valve damage
Sterile vegetation in hypercoagulable state with
no infection is called non-bacterial thrombotic
endocarditis
33
Fate of thrombus
o Propagation
o Embolization
o Dissolution
o Organization and recanalization

34
 Propagation=>Thrombi accumulate additional platelets and
fibrin, eventually causing vessel obstruction.
 Embolization=> Thrombi dislodge or fragment and are
transported elsewhere in the vasculature.
 Dissolution=>Thrombi are removed by fibrinolytic activity.
 Organization and recanalization=>Thrombi induce
inflammation and fibrosis (organization).
o These can eventually recanalize (re-establishing some degree
of flow), or they can be incorporated into a thickened vessel
wall.
35
Thrombi are clinically significant in that:
o Cause obstruction of arteries and veins
o They are possible source of emboli

36
Venous thrombosis(phlebothrombosis)
•Affects veins of the lower extremities in 90% of the
cases
A. superficial venous thrombosis
•Usually occurs in saphenous system particularly
when there are varicosities
•Causes local edema, pain, and tenderness
becomes symptomatic but rarely embolize
37
• Local edema due to impaied venous drainage
predispose that involved overlying skin to
infection after slight trauma, developing a
condition known as varicose ulcer.

38
 B. Deep venous thrombosis
•Are more serious as they embolize
•Usually with in deep veins with in the calf muscles
•Although they may cause local pain edema, unlike
superficial vein thrombosis, they are entirely
asymptomatic in 50% of patients.
•Since deep vein obstruction rapidly get relieved by
collateral bypass channels
39
 Conditions associated with DVT
oTRAUMA, SURGERY, BURNS result in:
•Reduced physical activity leading to stasis
•Injury to vessels
•Release of procoagulant substance from the tissue
oPregnancy and puerperal state increase coagulation
factors and reduced synthesis of antithrombotics

40
• Debilitating conditions and wasting diseases
such as cancers

41
 Arterial and cardiac thrombosis
•Atherosclerosis is the major initiator of
thrombosis related to abnormal vascular flow and
loss of endothelial integrity
•Myocardial infarction is related to dyskinetic
contraction of the myocardium as well as damage
to the adjacent endocardium and cardiac thrombi
can arise
42
RHD may arise in atrial mural thrombi due to
mitral valve stenosis followed by left atrial
dilation
In addition to obstructive features, arterial
thrombi may embolize to any tissues
But particularly common in the :
-brain, kidney, spleen because of their large
volume of inflow of blood
43
 Embolism
o Is a process in which a detached intravascular solid,
liquid or gaseous mass is carried by blood to sites
distant from its point of origin
o 99% source is thrombus
o Rare forms of emboli include
• Fat globules
• Bubbles of air
• Amniotic fluid

44
• Infected foreign material
• Bits of bone marrow
• Platelets aggregation

45
Emboli lodge In vessels too small to permit
further passage, resulting in partial or complete
vascular occlusion
The potential consequence of this is ischemic
necrosis of distal tissues known as infarction
Depending on the site of origin, emboli may
lodge in the pulmonary or systemic circulations
46
 Pulmonary thromboembolism
o In more than 95% instance venous emboli
originates from deep leg vein thrombosis
o The effect of Pulmonary thromboembolism
depends on:
• The size of the embolus
• The state of pulmonary circulation
o More pulmonary emboli i.e. 60-80% are clinically
silent because they are very small
47
 Systemic thromboembolism
Refers to emboli travelling within arterial
circulation
Most (80%) arise from intracardiac mural
thrombi, 2/3 of which are associated with left
ventricular wall infarcts and another quarter
with dilated left atria secondary to rheumatic
VHD.
48
o REMINDER ARISE FROM
• Aortic aneurysm
• Thrombi on ulcerated atherosclerotic plaques
• Fragmentation of valvular vegetations
o Unlike venous emboli, which lead to lodge
primarily in one vascular bed(lung), arterial
thrombi can travel to a wide variety of sites
49
o The major sites for arteriolar embolization
are:
• Lower extremities(75%)
• Brain(10%)
• The rest in the intestines, kidneys, and spleen

50
 Crossed embolism
Occurs in the presence of foramen ovale
when an embolus is transferred from the right
to the left side of the heart, then to the
systemic circulation

51
 Fat embolism
Usually follows fractures of bones and other
types of tissue injury, globules of fat usually
enters the circulation

52
Although traumatic fat embolism occur,
usually it is asymptomatic in most cases and
fat is removed

53
 INFARCTION
 An infarct is an area of ischemic necrosis caused by occlusion
of either the arterial supply or the venous drainage in a
particular tissue.
 Nearly 99% of all infarcts result from thrombotic or embolic
events, and almost all result from arterial occlusion.
 Occasionally, infarction may also be caused by other
mechanisms, such as local vasospasm, expansion of an
atheroma secondary to intraplaque hemorrhage, or extrinsic
compression of a vessel (e.g., by tumor).

54
Uncommon causes include vessel twisting (e.g.,
in testicular torsion or bowel volvulus), vascular
compression by edema or entrapment in a hernia
sac, or traumatic vessel rupture.
Although venous thrombosis can cause
infarction, it more often merely induces venous
obstruction and congestion.
55
Usually, bypass channels open rapidly after the
occlusion forms, providing some outflow from
the area that, in turn, improves the arterial
inflow.
Infarcts caused by venous thrombosis are more
likely in organs with a single venous outflow
channel (e.g., testis and ovary).
56
 Morphology
Infarcts are classified on the basis of their color
(reflecting the amount of hemorrhage) and the
presence or absence of microbial infection.
Therefore, infarcts may be either red
(hemorrhagic) or white (anemic) and may be
either septic or bland.

57
 Red infarcts: occur
(1) with venous occlusions (such as in ovarian torsion);
(2) in loose tissues (such as lung) that allow blood to
collect in the infarcted zone;
(3) in tissues with dual circulations such as lung and
small intestine, permitting flow of blood from an
unobstructed parallel supply into a necrotic area (such
perfusion not being sufficient to rescue the ischemic
tissues);
58
 (4) in tissues that were previously congested
because of sluggish venous outflow;
(5) when flow is re-established to a site of
previous arterial occlusion and necrosis (e.g.,
fragmentation of an occlusive embolus or
angioplasty of a thrombotic lesion).
59
 White infarcts
occur with arterial occlusions or in solid organs (such
as heart, spleen, and kidney), where the solidity of the
tissue limits the amount of hemorrhage that can seep
into the area of ischemic necrosis from adjoining
capillary beds
Septic infarctions occur when bacterial vegetations
from a heart valve embolize or when microbes seed an
area of necrotic tissue. 60
 Factors That Influence Development of an
Infarct
The major determinants of the eventual
outcome include the nature of the vascular
supply, the rate of development of the
occlusion, vulnerability to hypoxia, and the
oxygen content of blood.

61
 Nature of the Vascular Supply
 The availability of an alternative blood supply is the most
important determinant of whether occlusion of a vessel will
cause damage.
 For example, lungs have a dual pulmonary and bronchial
artery blood supply; thus, obstruction of small pulmonary
arterioles does not cause infarction in an otherwise healthy
individual with an intact bronchial circulation.
 In contrast, renal and splenic circulations are end-arterial,
and obstruction of such vessels generally causes infarction

62
Rate of Development of Occlusion
 Slowly developing occlusions are less likely to cause
infarction because they provide time for the
development of alternative perfusion pathways.

63
 Vulnerability to Hypoxia
 The susceptibility of a tissue to hypoxia influences the
likelihood of infarction.
 Neurons undergo irreversible damage when deprived
of their blood supply for only 3 to 4 minutes.
 Myocardial cells, though hardier than neurons, are also
quite sensitive and die after only 20 to 30 minutes of
ischemia.
 In contrast, fibroblasts within myocardium remain
viable after many hours of ischemia.
64
 Oxygen Content of Blood
The partial pressure of oxygen in blood also
determines the outcome of vascular occlusion.
 Partial flow obstruction of a small vessel in an
anemic or cyanotic patient might lead to tissue
infarction, whereas it would be without effect
under conditions of normal oxygen tension.

65
 SHOCK
• A state in which the circulatory system fails
to maintain adequate cellular perfusion.
• resulting in widespread reduction in delivery
of oxygen & other nutrients to tissues.

66
 Ctd...
• Regardless of the underlying pathology, shock
constitutes systemic hypoperfusion owing to
reduction either in cardiac out put or in the
effective circulating blood volume.
• The end results are hypotension followed by
impaired tissue perfusion & cellular hypoxia.
• The different types of shock are:
67
 1. Hypovolumic shock
• Is the reduction in circulating blood volume.
• results in reduction in preload leading to
inadequate left ventricular filling, reflecting as a
decreased in left & right ventricle end diastolic
volume & pressure, culminating in decreased
cardiac out put
• Causes include hemorrhage, fluid loss from
burns, diarrhea & vomiting
68
 2. Cardiogenic shock
• It results from myocardial pump failure
(severe depression of cardiac performance)
• Causes:
1. Myopathic
• Acute myocardial infarction
• Myocarditis
• Dilated & hypertrophic cardiomyopathy
• Myocardial depression in septic shock
69
 2. Mechanical
I. Intracardiac
a. Left ventricle out flow obstruction e.g.
Aortic stenosis
b. Reduction in forward cardiac out put e.g.
AR, MR
c. Arrhythmia
70
 Ctd...
II. Extracardiac
-It is an obstructive shock
a. Pericardial tamponade
b. Tension pneumothorax
c. Acute massive pulmonary embolism
d. Severe pulmonary hypertension
71
 3. Distributive shock
• Refers to a group of shock subtypes caused by
profound peripheral vasodilation despite normal
or high cardiac out put.
• Causes
Septic shock
Anaphylactic shock
Neurogenic shock
72
 Septic shock
Sepsis
• Definition: is a systemic response to severe infection.
• Mediated via macrophage derived cytokines that target end organ
receptors in response to infection or
• Systemic inflammatory response syndrome (SIRS) that has
suspected or proven microbial etiology.
• SIRS is a sepsis-like condition associated with systemic
inflammation that may be triggered by a variety of nonmicrobial
insults, such as burns, trauma, and/or pancreatitis

73
 Ctd...
• Septic shock: a kind of shock caused by
systemic microbial infection. Or
• Sepsis with:
- Hypotension
- Organ dysfunction
- Unresponsive to fluid administration
74
 Neurogenic shock
• Shock may occur in setting of anesthetic accident or
spinal cord injury.
• Occurs due to loss of vascular tone & peripheral
pooling of blood.
Anaphylactic shock
• It is initiated by a generalized IgE mediated
hypersensitivity response, is associated with systemic
vasodilation & increased vascular permeability.

75
76
 Morphology
• All organs affected in sever shock. The cellular & tissue
change induced by shock are essentially those of
hypoxic injury so manifest as organ dysfunction.
Heart
• Focal or widespread coagulation necrosis
• May manifest subendocardial necrosis
• Myocardial infarction

77
 Lung
• In established shock pulmonary function may
deteriorate rapidly due to a combination of
causes:
Pulmonary edema
Alveolar collapse

78
 Ctd...
• leucocytes accumulation as a result of
infection.
• Infection causes inflammation with exudation
of protein cause fibrin to alveolar space.
• This features collectively known as shock lung
or ARDS
79
 Kidney
• Exhibits extensive tubular ischemic injury, i.e.
acute tubular necrosis.
• Manifested as oligouria, anuria & electrolyte
disturbance.

80
 Clinical course of shock
• Pt may manifest as having:
A weak & rapid pulse
Tachypnea
Cool, clammy, cyanotic skin
- In septic shock, skin initially is warm &
fleshed because of peripheral vasodilatation.
81
 Ctd...
• The pt may present with confusion,
restlessness, decrease in urine out put, coma
& death.
• The prognosis varies with the origin of shock
& its duration.
• 80-90% of young pts with hypovolumic shock
survive where as cardiogenic shock & septic
shock carry mortality rate up to 75%.
82
 Hemodynamic
Disorders - 2

Dirar Medhanie, MD, Pathologist

Bleeding Disorders
 BLEEDING DISORDERS
• Characterized clinically by abnormal
bleeding
• Spontaneous Vs Trauma

85
 Hemostasis
• Hemostasis is the process by which vascular integrity
is maintained.
• Hemostasis is dependent on:
– Vascular endothelium,
– Platelets
– von Willebrand factor (vWF) and
– Soluble plasma proteins: pro-, anticoagulants and
fibrinolytics
86
 Hemostasis
• Normal hemostasis requires that platelets,
endothelial cells, coagulation factors and
endogenous anticoagulants and thrombolytics
maintain a resting non-thrombotic state but
that they can respond instantly to vascular
damage and form a clot.

87
 Small Vessel Hemostasis Response to Injury
Vasoconstriction - reflex neurogenic mechanisms and
Vascular Phase endothelin,

Platelet Adhesion - GPIb to vWF

Conformational shape change-

Platelet Phase Platelet Release of Aggregating agents (ADP)
Platelet Synthesis of TXA2
Temporary Platelet Thrombus

Coagulation Phase Formation of Stable Platelet Thrombus

Dissolution of Platelet Thrombus

Fibrinolytic Phase
Re-establishment of Blood Flow 88
 Megakaryocyte Sequence

89
 Megakaryocyte Sequence

90
91
92
 CLOTTING CASCADE
Clotting factors, act like a row of dominoes toppling
against each other to create a chain reaction.
If one of the factors is missing this chain reaction
cannot proceed.
94
95
e Fibrinolytic System illustrating various plasminogen activators and Inhibito
96
97
 Hemostasis
• Maintaining normal hemostasis depends on all of
these factors working in concert, and alterations
in the system, either inherited or acquired, will
lead to dysregulation of normal hemostasis
  Bleeding or Thrombosis.

98
 Bleeding Disorders
• Defects in hemostasis occur when the balance
of procoagulant and anticoagulant activities
tilts toward one or the other.
– If hemostasis fails to restore an injured vessel’s
integrity, the result is bleeding.
– Inability to maintain the fluidity of blood causes
thrombosis.
99
 Vascular Disorders
-Senile Purpura
-Scurvy Principal Causes of Bleeding
-Purpura Simplex
-Glucocorticoid Excess Platelet Abnormalities
-Dysproteinemias -Thrombocytopenia
-Allergic Purpura (HSP) -Qualitative Disorders
Coagulation Factor Deficiencies - Inherited
-Inherited - Glanzman Thrombasthenia
- vWD - Bernar-Soulier Syndrome
- Hemophilia A - Storage pool Diseases
- Hemophila B - Acquired
-Acquired - Uremia
- Vit K Def - Drugs
- Liver Disease - MPDs
- DIC - Liver disease 100
 Tests for Bleeding Disorders
 Bleeding time
• Represents the time taken for a standardized
skin puncture to stop bleeding
• Assessment of platelet response to limited
vascular injury
• Varies from 2 to 9 minutes
101
 Tests for Bleeding Disorders
 Platelet counts
• Electronic particle counter
• 150,000 - 450,000 per μL
 Prothrombin time (PT)
• adequacy of the extrinsic and common coagulation
pathways.
• time needed for plasma to clot with exogenously added
source of tissue thromboplastin (e.g., brain extract) and Ca
ions. Normal 10-15seconds
• deficiency of factors V, VII, or X, prothrombin, or fibrinogen
102
 PTT
PT XII
VII XI
IX
VIII
X

II

103
Fibrin Clot
 Tests for Bleeding Disorders
 Partial thromboplastin time (PTT)
• assess the integrity of the intrinsic and common clotting
pathways
• deficiency of factors V, VIII, IX, X, XI, or XII or prothrombin
or fibrinogen or an acquired inhibitor (typically an
antibody) that interferes with the intrinsic pathway.
• Normal 25-40seconds

104
 PTT
PT XII
VII XI
IX
VIII
X

II

105
Fibrin Clot
 Tests for Bleeding Disorders

 Thrombin time
 Time for Thrombin To Convert
Fibrinogen Fibrin

NORMAL 9-13 SECS

Bleeding Disorders
 Bleeding Disorders
• Vascular disorders ( ↑ fragility )
– Increased fragility of the vessels is associated with

 Infectious
 Drugs
 severe vitamin C deficiency (scurvy),
 Perivascular amyloidosis,
 chronic glucocorticoid use,
 connective tissue disorders, and
 a large number of infectious and hypersensitivity vasculitides.
108
 Bleeding Disorders
• Vascular disorders ( ↑ fragility )
– A hemorrhagic diathesis that is purely the result of vascular fragility
is characterized by

(1) the appearance of petechiae & ecchymoses in the skin and

mucous membranes (from minor trauma),

(2) a normal platelet count and tests of coagulation (PT, PTT), and

(3) a bleeding time that is usually normal.

109
Pt with Scurvy

110
 Bleeding Disorders
Platelet Disorders
 Thrombocytopenia
 Thrombocytopenia, defined as platelet counts under 150,000/
μL, results from:
– Decreased production

– Decreased survival

– Increased utilization

111
 Bleeding Disorders
Platelet Disorders
 Impaired platelet function

• Uremia
• after aspirin ingestion,
• myeloproliferative disorders,
• von Willebrand disease
112
 Bleeding Disorders
Platelet Disorders:
Characteristics
– Petechiae, purpura and ecchymoses,
– Easy bruising,
– Nosebleeds,
– Excessive bleeding from minor trauma,
– Menorrhagia.
– PT and PTT are normal,

– Bleeding time is always prolonged.

113
114
Ecchymosis
116
 Bleeding Disorders
Coagulation disorders
•Derangement of clotting factors
– Congenital coagulation disorders

•PT, PTT, or both prolonged

•Bleeding time is normal.

117
 Bleeding Disorders
Coagulation disorders: characteristics

– Petechiae are usually absent.

– Massive hemorrhage may follow operative or dental

procedures or severe trauma.

– Hemorrhages into areas of the body subject to

trauma, such as in the joints of the lower extremities
or muscle, are characteristic. 118
Clinical Features of Bleeding Disorders
Platelet disorders Coagulation
disorders

Site skin, mucosa deep

Petechiae Yes No
Ecchymoses (“bruises”) Small, superficial Large, deep
Hemarthrosis / muscle bleeding Extremely rare Common
Bleeding after cuts & scratches Yes No
Bleeding after surgery or trauma Immediate, Delayed (1-2 days),
usually mild often severe
 Platelet Coagulation

Petechiae, Purpura Hematoma, Joint bl.

 Bleeding Disorders
Mixed/Consumption: DIC

Involves consumption of both platelets and the clotting

factors

Features of both thrombocytopenia and a coagulation

disorder.

•von Willebrand disease also involves derangements in both

modalities.
121
Platelet Disorders

- Thrombocytopenia

122
 THROMBOCYTOPENIA
• 150,000 cells/μL or less*
• 20,000 to 50,000 cells/μL are associated with an increased risk of
post-traumatic bleeding
• spontaneous bleeding when counts fall below 20,000 cells/μL.

• What is the risk???

123
 THROMBOCYTOPENIA : Causes
• Are confined to:

 Reduced production,
 Hereditary or acquired
 Increased consumption
 Active bleeding or in DIC
 Increased destruction of platelets
 Autoimmune, drug induced or infectious
 Other includes:-
 Sequestration (in patients with splenomegaly),
 Dilutional* Massive transfusions can produce a dilutional thrombocytopenia

124
Decreased Production of Platelets
-Selective impairment of platelet production
- Drug-induced: alcohol, thiazides, cytotoxic drugs
- Infections: measles, human immunodeficiency virus
(HIV)
-Nutritional deficiencies
- B12, folate deficiency (megaloblastic anemia)
-Bone marrow failure
- Aplastic anemia
-Bone marrow replacement
- Leukemia, disseminated cancer, granulomatous
disease
-Ineffective hematopoiesis
- Myelodysplastic syndromes
125
Decreased Platelet Survival
Immunologic destruction
- Primary autoimmune
- Chronic immune thrombocytopenic purpura
- Acute immune thrombocytopenic purpura
- Secondary autoimmune
- Systemic lupus erythematosus, B-cell lymphoid neoplasms
- Autoimmune: posttransfusion and neonatal
- Drug-associated: quinidine, heparin, sulfa compounds
- Infections: HIV, infectious mononucleosis (transient, mild), dengue fever
Nonimmunologic destruction
- DIC, Thrombotic microangiopathies, Giant hemangiomas
126
 Immune Thrombocytopenic
Purpura
A disorder of autoimmune origin.

Classification:
•An acute, self-limited form occurs in children following
viral infections(acute Primary ITP).

•Most patients are adult females between the ages of

20 and 40 years (cd as "chronic Primary ITP.“)
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 Immune Thrombocytopenic
Purpura: Chronic
• Can occur in the
• Setting of a variety of conditions and exposures
(secondary ITP)
– SLE, HIV infection, and B-cell neoplasms such as chronic
lymphocytic leukemia
 Absence of any known risk factors (primary or
idiopathic ITP).

128
 Immune Thrombocytopenic
Purpura: Chronic
• In about 80%, antiplatelet immunoglobulins directed
against platelet membrane glycoproteins IIb-IIIa or Ib-
IX complexes.
– IgG is the Ab type in the majority
– antiplatelet antibodies act as opsonins that are recognized
by IgG Fc receptors expressed on phagocytes.
• The autoantibodies may bind to megakaryocytes and
impair platelet production as well.
– Megakaryocyte number does not decrease, or may even
moderately increase
129
 Immune Thrombocytopenic
Purpura: Pathogenesis
• The spleen is the major site of production of the
antiplatelet antibodies and destruction of the
IgG-coated platelets.
– Splenectomy is followed by the return of normal
platelet counts and complete remission.

• The spleen usually appears remarkably normal.

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 Immune Thrombocytopenic
Purpura : Morphology
• Peripheral smear: Giant, reticulated platelets (Young)
• The marrow may appear normal but usually reveals increased
numbers of megakaryocytes, some of which have only a
single nucleus and are thought to be young.

• Marrow examination may be used to rule out

thrombocytopenia resulting from marrow failure.
• Otherwise ITP is a diagnosis of exclusion since the
morphologic changes are non-specific

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132
133
 Immune Thrombocytopenic
Purpura: C/F
• Usually insidious.
• Manifestations are
 petechiae,
 easy bruisability,
 epistaxis,
 gum bleeding, and
 hemorrhages after minor trauma.

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 Immune Thrombocytopenic
Purpura:Diagnosis
• Based on:
 Clinical features,
 The presence of thrombocytopenia,
 Marrow examination,
 Increased megakaryocytes*
 Exclusion of secondary causes of thrombocytopenia.
• Test for antiplatelet antibodies (are not widely available).
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136
 Heparin-Induced Thrombocytopenia
• Moderate to severe thrombocytopenia develops in 3% to 5% of
individuals treated with unfractionated heparin after 1 to 2 weeks of
Rx.
• It results from the formation of antibodies that recognize complexes of
heparin and PF4 on the surface of platelets and endothelial cells
• This activates platelets and induces their aggregation.
• IgG bound platelets destroyed by the spleen ( Thrombocytopenia)
• Although thrombocytopenia is the most common manifestation,
thrombosis ( endothelial activation ) is the most serious complication.

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 Heparin-Induced Thrombocytopenia
• Diagnosis requires the demonstration of anti–
PF4-heparin antibodies.
• Low-molecular-weight heparin preparations
induce HIT less frequently, and other classes of
anticoagulants such as direct inhibitors of factor
X and thrombin may also obviate the risk
l
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139
 DISSEMINATED INTRAVASCULAR
COAGULATION
• An acute, subacute, or chronic thrombohemorrhagic
disorder
• Secondary complication in a variety of diseases.

• Caused by the systemic activation of the coagulation

pathways, leading to the formation of microthrombi
throughout the microcirculation.

• There is consumption of platelets and coagulation factors

and, secondarily, activation of fibrinolysis
140
 DIC: Etiology and Pathogenesis
• Two major mechanisms can trigger DIC:

1. The release of tissue factor or thromboplastic

substances into the circulation, &

2. Widespread endothelial cell damage

141
 DIC: Etiology and Pathogenesis
Sources for release of thromboplastic substance
• Placenta in obstetric cxns,
• Cytoplasmic granules of acute promyelocytic leukemia
cells, or mucin-secreting adenoca cells.
• Carcinomas - proteolytic enzymes, and other still-
undefined tumor products.
• Some tumors express tissue factor on the cell
membrane.
• G-ve and G+ve sepsis, endotoxins or exotoxins cause
increased synthesis, surface expression, and release of
tissue factor from monocytes.
• Activated monocytes release IL-1 and tumor necrosis
factor 142
 DIC: Etiology and Pathogenesis
• Endothelial cell injury results in exposing subendothelial
collagen and vWF, and can cause release of tissue factor.
• Endothelial injury can be produced by
The deposition of ag-ab complexes (e.g. in SLE)
Temperature extremes (e.g. in heat stroke or burns)
Infections (e.g. meningococci and rickettsiae)

DIC is a frequent complication of gram-negative

sepsis. 143
 DIC has two consequences:-
1. Widespread fibrin deposition within the
microcirculation which leads to ischemia and
hemolysis of RBCs (microangiopathic hemolytic
anemia)

2. Bleeding diathesis results from the depletion of

platelets and clotting factors, and secondary
release of plasminogen activators
144
Pathophysiology of disseminated
intravascular coagulation 145
 DIC: Morphology
• Microthrombi are found principally in the arterioles and
capillaries of the kidneys, adrenals, brain, spleen, liver, and
heart.
• But no organ is spared.

• Involvement of the adrenal glands can produce Waterhouse-

Friderichsen syndrome.

• It has been suggested that DIC contributes to Sheehan

postpartum pituitary necrosis.

146
 DIC: Clinical Course
• Acute DIC (e.g., that associated with obstetric
complications) is dominated by a bleeding diathesis
• Chronic DIC (e.g., as occurs in an individual with cancer)
tends to present with symptoms related to thrombosis
• Shock, with acute renal failure, dyspnea, cyanosis,
convulsions, and coma.
• Hypotension is characteristic.
• Most present with bleeding diathesis

147
 DIC: Lab Findings
• Laboratory evaluation reveals
thrombocytopenia, prolongation of PT and PTT
• Fibrin split products are increased
• Fibrinogen level will be depleted

148
 DIC: Rx and prognosis
• Life threatening
• Rxed - fresh-frozen plasma.
• Treat underlying disorder

149
 DIC: Rx and prognosis
• Variable prognosis depending on
 underlying disorder,
 degree of intravascular clotting,
 activity of the mononuclear phagocyte system, and
 the amount of fibrinolysis.

150