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MICHELLE ANNE M. ENCINAS, MD DPSP
BLEEDING DISORDERS
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Introduction
y Excessive bleeding can result from
y (1) increased fragility of vessels
y (2) platelet deficiency or dysfunction
y
(3) derangement of coagulationy (4) combinations of these
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Review of Hemostasis
y Normal hemostasis is the result of a set of well-regulated
processes that accomplish two important functions
y (1) They maintain blood in a fluid, clot-free state in normal
vessels
y (2) They are poised to induce a rapid and localized hemostatic plug
at a site of vascular injury.
y The pathologic opposite to hemostasis is thrombosis;
(formation of a blood clot (thrombus) in uninjured vasculature
or thrombotic occlusion of a vessel after relatively minor
injury)
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Bleeding Disorders: Hemorrhagic
Diatheses
y Tests used to evaluate different aspects of hemostasis are the
following:
y Bleeding time
y Platelet counts
y Prothrombin time (PT)
y Partial thromboplastin time (PTT)
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Bleeding Time
y Measures the time taken for a standardized skin puncture to
stop bleeding
y Provides an in vivo assessment of platelet response to limited
vascular injuryy Reference range depends on the actual method employed and
varies from 2 to 9 minutes
y Prolongation generally indicates a defect in platelet numbers
or function
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Bleeding Timey Fraught with variability and poor
reproducibility
y New instrument-based assay
systems such as platelet function
analyzer-100 (PFA-100) providea quantitative measure of platelet
function under conditions of
high shear stress
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PFA-100
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Platelet Counts
y Obtained on anticoagulated blood using an electronic particle
counter
y Reference range is 150 to 300 103/L
y
Counts well outside this range need to be confirmed by avisual inspection of a peripheral blood smear
y Clumping of platelets can cause spurious
"thrombocytopenia" during automated counting
y High counts may be indicative of a myeloproliferativedisorder
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Prothrombin Time (PT)
y Tests the extrinsic and common coagulation pathways
y The clotting of plasma after addition of an exogenous source
of tissue thromboplastin (e.g., brain extract) and Ca 2+ ions is
measured in secondsy Prolonged PT can result from deficiency or dysfunction of
factor V, factor VII, factor X, prothrombin, or fibrinogen
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Prothrombin Time (PT)
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Partial Thromboplastin Time (PTT)
y Tests the intrinsic and common clotting pathways
y The clotting of plasma after addition of kaolin, cephalin, and
calcium ions is measured in seconds
y
Kaolin serves to activate the contact-dependent factor XII,and cephalin substitutes for platelet phospholipids
y Prolongation of the PTT can be due to deficiency or
dysfunction of factor V, VIII, IX, X, XI, or XII, prothrombin,
or fibrinogen
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PT/PTT
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y More specialized tests are available to measure the levels of
specific clotting factors, fibrinogen, fibrin split products, the
presence of circulating anticoagulants, and platelet function
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BLEEDING DISORDERS CAUSED BY
VESSEL WALL ABNORMALITIES
y Sometimes called nonthrombocytopenic purpuras
y Induce small hemorrhages (petechiae and purpura) in the
skin or mucous membranes, particularly the gingivae
y
More significant hemorrhages can occur into joints, muscles,and subperiosteal locations or take the form of menorrhagia,
nosebleeds, gastrointestinal bleeding, or hematuria
y The platelet count, bleeding time, and results of the coagulation tests
(PT, PTT) are usually normal
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BLEEDING DISORDERS CAUSED BY
VESSEL WALL ABNORMALITIES
y Varied clinical conditions in which hemorrhages can be
related to abnormalities in the vessel wall include the
following:
y Infections
y Drug reactions
y Scurvy and the Ehlers-Danlos syndrome
y Henoch-Schnlein purpura
y Hereditary hemorrhagic telangiectasia
y Amyloid infiltration of blood vessels
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Infections
y Induce petechial and purpuric hemorrhages, but especially
implicated are meningococcemia, other forms of septicemia,
infective endocarditis, and several of the rickettsioses
y
Involved mechanism is presumably microbial damage to themicrovasculature (vasculitis) or disseminated intravascular
coagulation (DIC)
y Failure to recognize meningococcemia as a cause of petechiae
and purpura can be catastrophic for the patient
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Drug Reactions
y Sometimes induce cutaneous petechiae and purpura without
causing thrombocytopenia
y Vascular injury is mediated by drug-induced antibodies and
deposition of immune complexes in the vessel walls, leadingto hypersensitivity (leukocytoclastic) vasculitis
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Scurvy and the Ehlers-Danlos
syndrome
y Associated with microvascular bleeding resulting from
impaired formation of collagens needed for support of vessel
walls
y
Same mechanism may account for spontaneous purpuracommonly seen in the very elderly
y Predisposition to skin hemorrhages in Cushing syndrome, in
which the protein-wasting effects of excessive corticosteroid
production cause loss of perivascular supporting tissue, has a
similar etiology
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Henoch-Schnlein purpura
y A systemic hypersensitivity disease of unknown cause
characterized by a purpuric rash, colicky abdominal pain
(presumably due to focal hemorrhages into the
gastrointestinal tract), polyarthralgia, and acute
glomerulonephritis
y All these changes result from the deposition of circulating
immune complexes within vessels throughout the body and
within the glomerular mesangial regions
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Hereditary Hemorrhagic Telangiectasia
y An autosomal dominant disorder characterized by dilated,
tortuous blood vessels with thin walls that bleed readily
y Bleeding can occur anywhere in the body but is most
common under the mucous membranes of the nose(epistaxis), tongue, mouth, and eyes and throughout the
gastrointestinal tract
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Amyloid Infiltration of Blood Vessels
y Systemic amyloidosis is associated with perivascular
deposition of amyloid and consequent weakening of blood
vessel wall
y Most commonly observed in plasma cell dyscrasias and is
manifested as mucocutaneous petechiae
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BLEEDING RELATED TO REDUCED PLATELET
NUMBER: THROMBOCYTOPENIA
y Important cause of generalized bleeding
y Normal platelet counts range from 150,000 to 300,000/L
y A count below 100,000/L is generally considered to
constitute thrombocytopeniay Spontaneous bleeding does not become evident until the
count falls below 20,000/L
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BLEEDING RELATED TO REDUCED PLATELET
NUMBER: THROMBOCYTOPENIA
y Platelet counts in the range of 20,000 to 50,000/L canaggravate post-traumatic bleeding
y Bleeding resulting from thrombocytopenia alone is associated
with a prolonged bleeding time and normal PT and PTT
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Four Major Categories of
Thrombocytopenia
y Decreased production of platelets
y Decreased platelet survival
y Sequestration
yDilutional
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Thrombocytopenia
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Decreased Production ofPlatelets
y Can accompany generalized diseases of bone marrow such as
aplastic anemia and leukemias or result from diseases that
affect the megakaryocytes somewhat selectively
y Vitamin B12 or folic acid deficiency: poor development and
accelerated destruction of megakaryocytes within the bone
marrow (ineffective megakaryopoiesis) because DNA
synthesis is impaired
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Decreased Platelet Survival
y Important cause of thrombocytopenia can have an
immunologic or nonimmunologic etiology
y Immune conditions:
y
Platelet destruction is caused by circulating antiplateletantibodies or, less often, immune complexes.
y Antiplatelet antibodies can be directed against a self-antigen on
the platelets (autoantibodies) or against platelet antigens that
differ among different individuals (alloantibodies)
y Common antigenic targets of both autoantibodies andalloantibodies are the platelet membrane glycoprotein
complexes IIb-IIIa and Ib-IX
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Decreased Platelet Survival
y Autoimmune thrombocytopenias
y Include idiopathic thrombocytopenic purpura, certain drug-
induced thrombocytopenias, and HIV-associated
thrombocytopenias.
y Alloimmune thrombocytopenias arise when an individual is
exposed to platelets of another person (blood transfusion or
during pregnancy)
y In pregnancy, neonatal or even fetal thrombocytopenia occurs
by a mechanism analogous to erythroblastosis fetalis
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Decreased Platelet Survival
y Nonimmunologic destruction of platelets
y May be caused by mechanical injury, in a manner analogous to red
cell destruction in microangiopathic hemolytic anemia
y Underlying conditions are also similar, including prosthetic
heart valves and diffuse narrowing of the microvessels (e.g.,
malignant hypertension)
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Sequestration
y Thrombocytopenia, usually moderate in severity, may
develop in any patient with marked splenomegaly, a
condition sometimes referred to as hypersplenism
y The spleen normally sequesters 30% to 40% of the body's
platelets, which remain in equilibrium with the circulating
pool
y When necessary, hypersplenic thrombocytopenia can be
ameliorated by splenectomy
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Immune Thrombocytopenic Purpura
(ITP)
y Can occur in the setting of a variety of conditions and
exposures (secondary ITP) or in the absence of any known
risk factors (primary or idiopathic ITP)
y Two clinical subtypes of primary ITP, acute and chronic
y Both are autoimmune disorders in which platelet destruction
results from the formation of antiplatelet autoantibodies
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Immune Thrombocytopenic Purpura
(ITP): Secondary Forms
y Immunologically mediated destruction of platelets (immune
thrombocytopenia) occurs in many different settings,
including systemic lupus erythematosus, acquired
immunodeficiency syndrome (AIDS), after viral infections,
and as a complication of drug therapy
y Mimic the idiopathic autoimmune variety
y Diagnosis of this disorder should be made only after
exclusion of other known causes of thrombocytopenia
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Immune Thrombocytopenic Purpura
(ITP): Chronic ITP
y Caused by the formation of autoantibodies against platelet
membrane glycoproteins, most often IIb-IIIa or Ib-IX
y Antibodies reactive with these membrane glycoproteins can
be demonstrated in theplasma as well as bound to theplatelet
surface (platelet-associated immunoglobulins) in
approximately 80% of patients
y Majority of cases, the antiplatelet antibodies are of the IgG
class
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Immune Thrombocytopenic Purpura
(ITP): Chronic ITP
y Mechanism of platelet destruction is similar to that seen in
autoimmune hemolytic anemias
y Opsonized platelets are rendered susceptible to phagocytosis
by the cells of the mononuclear phagocyte system
y 75% to 80% of patients are remarkably improved after
splenectomy:
y Spleen is the major site of removal of sensitized platelets and
y Spleen source of antibodies
y Megakaryocytes may be damaged by autoantibodies
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Immune Thrombocytopenic Purpura
(ITP): Chronic ITP
Morphology: Spleen
y Normal in size
y Congestion of the sinusoids and hyperactivity and
enlargement of the splenic follicles, manifested by theformation of prominent germinal centers
y Scattered megakaryocytes are found within the sinuses and
sinusoidal walls (mild form of extramedullary hematopoeisis)
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Immune Thrombocytopenic Purpura
(ITP): Chronic ITP
Morphology: Bone Marrow
y Modestly increased number of megakaryocytes
y Some are apparently immature, with large, nonlobulated,
single nucleiy Importance of bone marrow examination is to rule out
thrombocytopenias resulting from bone marrow failure
y Decrease in the number of megakaryocytes argues against the
diagnosis of ITP
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Megakaryocyte in a BM aspirate
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Immune Thrombocytopenic Purpura
(ITP): Chronic ITP
Clinical Features
y Occurs most commonly in adult women younger than age 40
years
y F
emale-to-male ratio is 3:1y Insidious in onset and is characterized by bleeding into the
skin and mucosal surfaces
y Cutaneous bleeding is seen in the form ofpinpoint hemorrhages
(petechiae)
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Immune Thrombocytopenic Purpura
(ITP): Chronic ITP
y Petechiae can become confluent, giving rise to ecchymoses
y History of easy bruising, nosebleeds, bleeding from the
gums, and hemorrhages into soft tissues from relatively
minor trauma
y May manifest first with melena, hematuria, or excessive
menstrual flow
y Subarachnoid hemorrhage and intracerebral hemorrhage are
serious consequences of thrombocytopenic purpura but,fortunately, are rare in treated patients
y Splenomegaly and lymphadenopathy are uncommon
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ITP
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Immune Thrombocytopenic Purpura
(ITP): Chronic ITP
y Not specific for this condition but rather reflective ofthrombocytopenia
y Low platelet count and normal or increased megakaryocytesin the bone marrow
y Accelerated thrombopoiesis often leads to the formation ofabnormally large platelets (megathrombocytes), detectedeasily in a blood smear
y Bleeding time is prolonged, but PT and PTT are normal
yTests for platelet autoantibodies are not widely available
y Diagnosis sould be made only after other causes of plateletdeficiencies have been ruled out
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Immune Thrombocytopenic Purpura
(ITP): Chronic ITP
y Respond to immunosuppressive doses of glucocorticoids
y Splenectomy
y Refractory cases
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Acute Immune Thrombocytopenic
Purpura
y Caused by antiplatelet autoantibodies
y Disease of childhood occurring with equal frequency in both
sexes
y O
nset of thrombocytopenia is abrupt and is preceded inmany cases by a viral illness
y Usual interval between the infection and onset of purpura is
2 weeks
y
Self-limited, usually resolving spontaneously within 6 months
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Acute Immune Thrombocytopenic
Purpura
y Steroid therapy is indicated only if thrombocytopenia is
severe
y Approximately 20% of the children, usually those without a
viral prodrome, have persistent low platelet counts beyond 6
months and appear to have chronic ITP similar in most
respects to the adult disease
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Drug-Induced Thrombocytopenia:
Heparin-Induced Thrombocytopenia
y Can result from immunologically mediated destruction of
platelets after drug ingestion
y Drugs most commonly involved are quinine, quinidine,
sulfonamide antibiotics, and heparin
y Heparin-induced thrombocytopenia (HIT):
Thrombocytopenia occurs in approximately 5% of patients
receiving heparin
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Drug-Induced Thrombocytopenia:
Heparin-Induced Thrombocytopenia
y Most HIT develop so-called type I thrombocytopenia:
y Occurs rapidly after onset of therapy
y Modest in severity and clinically insignificant
y May resolve despite continuation of heparin therapy
y Most likely results from a direct platelet-aggregating effect of
heparin
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Drug-Induced Thrombocytopenia:
Heparin-Induced Thrombocytopenia
y Type II thrombocytopenia is more severe
y Occurs 5 to 14 days after commencement of therapy (or
sometimes sooner if the patient has been previously sensitized
to heparin)
y Can, paradoxically, lead to life-threatening venous and arterialthrombosis
y Caused by an immune reaction directed against a complex of
heparin and platelet factor 4, a normal component of platelet
granules that binds tightly to heparin
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Drug-Induced Thrombocytopenia:
Heparin-Induced Thrombocytopenia
y Appears that heparin binding modifies the conformation ofplatelet factor 4, making it susceptible to immunerecognition
y Binding of antibody to platelet factor 4 produces immune complexes
that activate platelets, promoting thrombosis even in the setting ofmarked thrombocytopenia
y Mechanism of platelet activation is not understood.Unlesstherapy is immediately discontinued, clots within largearteries may lead to vascular insufficiency and limb loss, andemboli from deep venous thrombosis can cause fatalpulmonary thromboembolism
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HIV-Associated Thrombocytopenia
y The most common hematologic manifestation of HIV
infection
y Impaired platelet production and increased destruction are
responsible
y CD4, the receptor for HIV on T cells, has also been
demonstrated on megakaryocytes, making it possible for
these cells to be infected by HIV
y Infected megakaryocytes are prone to apoptosis and are
impaired in terms of platelet production
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HIV-Associated Thrombocytopenia
y HIV infection also causes hyperplasia and dysregulation of B
cells, which predispose to the development of immune-
mediated thrombocytopenia
y Antibodies directed against platelet membrane glycoprotein
IIb-III complexes are detected in some patients' sera
y Autoantibodies, which sometimes cross-react with HIV-
associated gp120, are believed to act as opsonins, thus
promoting the phagocytosis of platelets by splenic phagocytes
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HIV-Associated Thrombocytopenia
y Some studies also implicate nonspecific deposition of
immune complexes on platelets as a factor in their premature
destruction by the mononuclear phagocyte system
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Thrombotic Microangiopathies: Thrombotic Thrombocytopenic
Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)
y Thrombotic microangiopathy:
y Encompasses a spectrum of clinical syndromes that includes
TTP and HUS
y TTP: pentad of fever, thrombocytopenia, microangiopathic
hemolytic anemia, transient neurologic deficits, and renalfailure
y HUS: also associated with microangiopathic hemolytic anemia
and thrombocytopenia but is distinguished from TTP by the
absence of neurologic symptoms, the prominence of acute renalfailure, and frequent affliction of children
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Thrombotic Microangiopathies: Thrombotic Thrombocytopenic
Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)
y Common fundamental feature in both of these conditions is
widespread formation of hyaline thrombi, comprised
primarily of platelet aggregates, in the microcirculation
y Consumption of platelets leads to thrombocytopenia, and the
intravascular thrombi provide a likely mechanism for the
microangiopathic hemolytic anemia and widespread organ
dysfunction
y Symptomatic TTP patients are often deficient in an enzyme
called ADAMTS 13
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Thrombotic Microangiopathies: Thrombotic Thrombocytopenic
Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)
y Enzyme is designated "vWFmetalloprotease" and itnormally degrades very high molecular weight multimers ofvon Willebrand factor (vWF)
y In the absence of this enzyme, very high molecular weight
multimers of vWF accumulate in plasma and, under somecircumstances, promote platelet microaggregate formationthroughout the microcirculation, leading to the symptoms ofTTP
y Superimposition of endothelial cell injury may predispose apatient to microaggregate formation, thus initiating orexacerbating TTP
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Thrombotic Microangiopathies: Thrombotic Thrombocytopenic
Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)
y Deficiency of ADAMTS 13 may be inherited or acquired
y Antibody that inhibits vWF metalloprotease is detected
y Inherited an inactivating mutation in the gene encoding this
enzyme
y HUS have normal levels of vWF metalloprotease: cause
infectious gastroenteritis caused by E. coli strain 0157:H7
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Thrombotic Microangiopathies: Thrombotic Thrombocytopenic
Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)
y Strain elaborates a Shiga-like
toxin that is absorbed from the
inflamed gastrointestinal mucosa
y Binds to and damages endothelial
cells in the glomerulus andelsewhere, thus initiating platelet
activation and aggregation
y Affected children present with
bloody diarrhea, and a few days
later HUS makes its appearance
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Thrombotic Microangiopathies: Thrombotic Thrombocytopenic
Purpura (TTP) and Hemolytic-Uremic Syndrome (HUS)
y Irreversible renal damage and death can occur in more severe
cases of HUS
y HUS can also be seen in adults following exposures that
damage endothelial cells (e.g., certain drugs, radiation
therapy)
y In TTP and HUS (unlike DIC), activation of the coagulation
cascade is not of primary importance, and hence results of
laboratory tests of coagulation, such as PT and PTT, are
usually normal
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BLEEDING DISORDERS RELATED TO
DEFECTIVE PLATELET FUNCTIONS
y Congenital or acquired
y Congenital disorders of platelet function can be classified into
three groups on the basis of the specific functional
abnormality:
y (1) defects of adhesion
y (2) defects of aggregation
y (3) disorders of platelet secretion (release reaction)
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BLEEDING DISORDERS RELATED TO DEFECTIVE
PLATELET FUNCTIONS: Congenital
Bernard-Soulier syndrome
y Caused by an inherited deficiency of the platelet membrane glycoprotein
complex Ib-IX
y Glycoprotein is a receptor for vWF and is essential for normal platelet
adhesion to subendothelial matrixGlanzmann's thrombasthenia
y Bleeding due to defective platelet aggregation; autosomal recessive
y Platelets fail to aggregate in response to ADP, collagen, epinephrine, or
thrombin due to deficiency or dysfunction of glycoprotein IIb-III, which
participates in the formation of "bridges" between platelets by binding
fibrinogen and vWF
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BLEEDING DISORDERS RELATED TO DEFECTIVE
PLATELET FUNCTIONS: Congenital
Disorders of platelet secretion
y Characterized by normal initial aggregation with collagen or
ADP, but subsequent responses, such as secretion of
thromboxanes and release of granule-bound ADP, are
impaired
y Underlying biochemical defects of these so-called storage pool
disorders are varied, complex, and beyond the scope of our
discussion
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BLEEDING DISORDERS RELATED TO
DEFECTIVE PLATELET FUNCTIONS: Acquired
Ingestion of aspirin and other nonsteroidal anti-inflammatory
drugs, which significantly prolongs the bleeding time
y Aspirin is a potent, irreversible inhibitor of the enzyme
cyclooxygenase, which is required for the synthesis of
thromboxane A2 and prostaglandins
y Mediators play important roles in platelet aggregation and
subsequent release reactions
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BLEEDING DISORDERS RELATED TO
DEFECTIVE PLATELET FUNCTIONS: Acquired
y Uremia
y The second condition exemplifying an acquired defect in
platelet function
y Pathogenesis of bleeding in uremia is complex and not fully
understoody Several abnormalities of platelet function are found
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HEMORRHAGIC DIATHESES RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
y Deficiency of every clotting factor has been reported to be
the cause of a bleeding disorder, with the exception of factor
XII deficiency, which does not cause bleeding
y Bleeding in factor deficiencies differs from platelet
deficiencies in that spontaneous petechiae or purpura are
uncommon
y Bleeding is manifested by large post-traumatic ecchymoses or
hematomas, or prolonged bleeding after a laceration or any
form of surgical procedure
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HEMORRHAGIC DIATHESES RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
Acquired disorders
y Usually characterized by multiple clotting abnormalities
y Vitamin K deficiency results in impaired synthesis of factors
II, VII, IX, and X and protein C
y Since the liver makes virtually all the clotting factors, severe
parenchymal liver disease can be associated with a
hemorrhagic diathesis
y
Disseminated intravascular coagulation produces a deficiencyof multiple coagulation factors
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HEMORRHAGIC DIATHESES RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
Hereditary deficiencies
y Have been identified for each of the clotting factors
y Deficiencies of factor VIII (hemophilia A) and of factor IX
(Christmas disease, or hemophilia B) are transmitted as
sex-linked recessive disorders
y Most others follow autosomal patterns of transmission
y These hereditary disorders typically involve a single clotting factor
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HEMORRHAGIC DIATHESES RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
y Course of history may have been
changed by a hereditary
coagulation defect present in the
intermarried royal families of
Great Britain and other parts of
Europe
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HEMORRHAGIC DIATHESES RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
Deficiencies ofFactor VIII-vWF Complex
y Hemophilia A and von Willebrand disease
y Plasma factor VIII-vWF is a complex made up of two separate
proteins (factor VIII and vWF) that can be characterized
according to functional, biochemical, and immunologic
criteria
Structure and function of factor VIII-von
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Structure and function of factor VIII von
Willebrand factor (vWF) complex
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HEMORRHAGIC DIATHESES RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
y vWF can be assayed by immunologic techniques or by the so-
called ristocetin agglutination test
y Assay can be performed with formalin-fixed platelets
y Measures the ability of ristocetin (developed as an antibiotic) to
promote the interaction between vWF and platelet membrane
glycoprotein Ib
y Multivalent ristocetin-dependent binding of vWF creates
interplatelet "bridges," leading to the formation of platelet
clumps (agglutination), an event easily measured in a devicecalled an aggregometer
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HEMORRHAGIC DIATHESES RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
y Two components of the factor VIII-vWF complex are
encoded by separate genes and synthesized in different cells
y vWF is produced by endothelial cells and megakaryocytes
and can be demonstrated in platelet -granules
y Endothelial cells are the major source of subendothelial and plasma
vWF
y Factor VIII is made in several tissues; sinusoidal endothelial
cells and Kupffer cells in the liver and glomerular and tubular
epithelial cells in the kidney appear to be particularly
important sites of synthesis
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HEMORRHAGIC DIATHESES RELATED TO
ABNORMALITIES IN CLOTTING FACTORS
y The two components of factor VIII-vWF complex, synthesized
separately, come together and circulate in the plasma as a unit that
serves to promote clotting as well as platelet-vessel wall interactions
necessary to ensure hemostasis
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Von Willebrand Disease
y Estimated frequency of 1%
y One of the most common inherited disorders of bleeding in
humans
y Characterized by spontaneous bleeding from mucous
membranes, excessive bleeding from wounds, menorrhagia,
and a prolonged bleeding time in the presence of a normal
platelet count
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Von Willebrand Disease
More than 20 variants of von Willebrand disease have been
described, which can be grouped into two major categories:
y Type 1 and type 3 von Willebrand disease
y Type 2 von Willebrand disease
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Von Willebrand Disease
Type 1 and type 3 von Willebrand disease
y Associated with a reduced quantity of circulating vWF.Type 1, an
autosomal dominant disorder, accounts for approximately
70% of all cases and is relatively mild
y Reduced penetrance and variable expressivity characterize
this type, and hence clinical manifestations are varied
y Type 3 (an autosomal recessive disorder) is associated with
extremely low levels of functional vWF, and the clinical
manifestations are correspondingly severe
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Von Willebrand Disease
Type 1 and type 3 von Willebrand disease
y Because a severe deficiency of vWF has a marked affect onthe stability of factor VIII, some of the bleedingcharacteristics resemble those seen in hemophilia
y The nature of the mutations in the vast majority of patientswith type 1 disease is poorly defined:
y Missense mutations
y Both alleles are affected by distinct mutations (compoundheterozygotes) producing an apparent dominant inheritance.
y Type 3 disease is associated with deletions or frameshiftmutations
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Von Willebrand Disease
Type 2 von Willebrand disease
y Characterized by qualitative defects in vWF
y Several subtypes, of which type 2A is the most common
y
Autosomal dominant disordery Because of missense mutations, the vWF formed is
abnormal, leading to defective multimer assembly
y Accounts for 25% of all cases and is associated with mild to
moderate bleeding
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Von Willebrand Diseasey Prolonged bleeding time despite a normal platelet count
y Plasma level of active vWF
y Because vWF stabilizes factor VIII by binding to it, adeficiency of vWF gives rise to a secondary decrease in factor
VIII levels; may be reflected by a prolongation of the PTT invon Willebrand disease types 1 and 3
y Patients with von Willebrand disease have a compound defectinvolving platelet function and the coagulation pathway
y
Adverse complications of factor VIII deficiency, such asbleeding into the joints, are uncommon
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Hemophilia A (Factor VIII Deficiency)
y The most common hereditary disease associated with seriousbleeding
y Caused by a reduction in the amount or activity of factor VIII(serves as a cofactor for factor IX in the activation of factor X
in the coagulation cascade)y Inherited as an X-linked recessive trait, and thus occurs in
males and in homozygous females
y Excessive bleeding has been described in heterozygousfemales, due to extremely unfavorable lyonization(inactivation of the normal X chromosome in most of thecells)
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Hemophilia A (Factor VIII Deficiency)
y Approximately 30% of patients have no family history; theirdisease is presumably caused by new mutations
y Exhibits a wide range of clinical severity that correlates well
with the level of factor VIII activity
y Those with less than 1% of normal activity develop severe
disease; levels between 2% and 5% of normal are associated
with moderate disease; and patients with 6% to 50% of activity
develop mild disease
y Variable degrees of factor VIII deficiency are largely
explained by heterogeneity in the causative mutations
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Hemophilia A (Factor VIII Deficiency)
y Deletions, nonsense mutations that create stop codons,splicing errors) have been documented
y Less commonly, severe hemophilia A is associated with point
mutations in factor VIII that impair the function of the
protein
y Mutations permitting some active factor VIII to be
synthesized are associated with mild to moderate disease
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Hemophilia A (Factor VIII Deficiency)
y Tendency toward easy bruising and massive hemorrhage aftertrauma or operative procedures
y Petechiae are characteristically absent
y Patients with hemophilia A typically have a normal bleeding
time, platelet count, and PT, and a prolonged PTT (point to
an abnormality of the intrinsic coagulation pathway)
y Factor VIII-specific assays are required for diagnosis
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Hemophilia A (Factor VIII Deficiency)
y In the face of factor VIII deficiency, fibrin deposition isinadequate to achieve hemostasis reliably
y Treatment of hemophilia A involves infusion of recombinant
factor VIII
y Approximately 15% of patients with low or absent factor VIII
develop antibodies that bind to and inhibit factor VIII
y With the availability of recombinant factor VIII, the risk of
HIV transmission has been eliminated
Hemophilia B (Christmas Disease
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Hemophilia B (Christmas Disease,
Factor IX Deficiency)
y Severe factor IX deficiency produces a disorder clinicallyindistinguishable from factor VIII deficiency (hemophilia A)
y Wide spectrum of mutations
y Inherited as an X-linked recessive trait and shows variable
clinical severity
y In about 14% of these patients, factor IX is present but
nonfunctional
y PTT is prolonged and the PT is normal, as is the bleeding
time
Hemophilia B (Christmas Disease
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Hemophilia B (Christmas Disease,
Factor IX Deficiency)
y Identification of Christmas disease (named after the firstpatient with this condition and not the holiday) is possible
only by assay of the factor levels
y Recombinant factor IX is used for treatment
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Hemophilia
DISSEMINATED INTRAVASCULAR
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
y An acute, subacute, or chronic thrombohemorrhagicdisorder occurring as a secondary complication in a variety of
diseases
y Characterized by activation of the coagulation sequence that
leads to the formation of microthrombi throughout themicrocirculation of the body, often in a quixotically uneven
distribution
y Sometimes the coagulopathy is localized to a specific organ
or tissue
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
y As a consequence of the thrombotic diathesis, there is consumption ofplatelets, fibrin, and coagulation factors and, secondarily, activation
of fibrinolytic mechanisms
y DIC can present with signs and symptoms relating to tissue
hypoxia and infarction caused by the myriad microthrombi oras a hemorrhagic disorder related to depletion of the
elements required for hemostasis ("consumption
coagulopathy")
DISSEMINATED INTRAVASCULAR
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
y Activation of the fibrinolytic mechanism aggravates thehemorrhagic diathesis
DISSEMINATED INTRAVASCULAR
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
Etiology and Pathogenesis
y A coagulopathy that occurs in the course of a variety of
clinical conditions
y Clotting can be initiated by either of two pathways:
y (1) the extrinsic pathway, which is triggered by the release of
tissue factor ("tissue thromboplastin")
y (2) the intrinsic pathway, which involves the activation of factor
XII by surface contact with collagen or other negatively charged
substances
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
y Both pathways, through a series of intermediate steps, resultin the generation of thrombin, which in turn converts
fibrinogen to fibrin
y Once activated at the site of injury, thrombin further
augments local fibrin deposition through feedback activationof the intrinsic pathway and inhibition of fibrinolysis
y As excess thrombin is swept away in the blood from sites of
tissue injury it is converted to an anticoagulant
DISSEMINATED INTRAVASCULAR
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
y Upon binding a surface protein called thrombomodulin onintact endothelial cells, thrombin becomes capable of
activating protein C, an inhibitor of the pro-coagulant factors
V and VIII
y Other important clot-inhibiting factors include the activationof fibrinolysis by plasmin and the clearance of activated
clotting factors by the mononuclear phagocyte system and
the liver
DISSEMINATED INTRAVASCULAR
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
y Could result from pathologic activation of the extrinsicand/or intrinsic pathways of coagulation or impairment of
clot-inhibiting influences
DISSEMINATED INTRAVASCULAR
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
y Two major mechanisms triggerDIC:
y (1) release of tissue factor or thromboplastic substances into the
circulation and
y (2) widespread injury to the endothelial cells.
DISSEMINATED INTRAVASCULAR
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
DISSEMINATED INTRAVASCULAR
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DISSEMINATED INTRAVASCULAR
COAGULATION (DIC)
y Endothelial injury, the other major trigger, can initiate DIC bycausing release of tissue factor, promoting platelet
aggregation, and activating the intrinsic coagulation pathway
y TNF is an extremely important mediator of endothelial cell
inflammation and injury in septic shock
y TNF up-regulates the expression of adhesion molecules on
endothelial cells and thus favors adhesion of leukocytes,
which in turn damage endothelial cells by releasing oxygen-
derived free radicals and preformed proteases
DISSEMINATED INTRAVASCULAR
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COAGULATION (DIC)
DISSEMINATED INTRAVASCULAR
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DISSEMIN TED INTR V SCUL R
COAGULATION (DIC)
Morphology
y In general, thrombi are found in the following sites in
decreasing order of frequency: brain, heart, lungs, kidneys,
adrenals, spleen, and liver
y No tissue is spared, and thrombi are occasionally found in
only one or several organs without affecting others
y Affected kidneys can reveal small thrombi in the glomeruli
that may evoke only reactive swelling of endothelial cells or,
in severe cases, microinfarcts or even bilateral renal corticalnecrosis
DISSEMINATED INTRAVASCULAR
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COAGULATION (DIC)
y Numerous fibrin thrombi may be found in alveolarcapillaries, sometimes associated with pulmonary edema and
fibrin exudation, creating "hyaline membranes" reminiscent
of acute respiratory distress syndrome
y In the central nervous system, fibrin thrombi can causemicroinfarcts, occasionally complicated by simultaneous
hemorrhage
DISSEMINATED INTRAVASCULAR
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COAGULATION (DIC)
y In meningococcemia, fibrin thrombi within themicrocirculation of the adrenal cortex are the likely basis for
the massive adrenal hemorrhages seen in Waterhouse-
Friderichsen syndrome
y Sheehan postpartum pituitary necrosis is a form of DICcomplicating labor and delivery
y In toxemia of pregnancy, the placenta exhibits widespread
microthrombi, providing a plausible explanation for the
premature atrophy of the cytotrophoblast andsyncytiotrophoblast encountered in this condition
DISSEMINATED INTRAVASCULAR
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COAGULATION (DIC)
Clinical Course
y Onset can be fulminant, as in endotoxic shock or amniotic
fluid embolism, or insidious and chronic, as in cases of
carcinomatosis or retention of a dead fetus
y About 50% of individuals with DIC are obstetric patients
having complications of pregnancy
y About 33% of the patients have carcinomatosis
DISSEMINATED INTRAVASCULAR
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COAGULATION (DIC)
y Microangiopathic hemolytic anemia; dyspnea, cyanosis, andrespiratory failure; convulsions and coma; oliguria and acute
renal failure; and sudden or progressive circulatory failure
and shock
y In general, acute DIC, associated with obstetric complications ormajor trauma, for example, is dominated by a bleeding diathesis,
whereas chronic DIC, such as occurs in cancer patients, tends to
present initially with thrombotic complications
DISSEMINATED INTRAVASCULAR
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COAGULATION (DIC)
y Accurate clinical observation and laboratory studies arenecessary for the diagnosis
y Prognosis is highly variable and depends, to a considerable
extent, on the underlying disorder
y Administration of anticoagulants or procoagulants
y Only definitive treatment is to remove or treat the inciting
cause whenever possible
DISSEMINATED INTRAVASCULAR
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COAGULATION (DIC)
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End.