Bleeding Disorders 2010

8/3/2019 Bleeding Disorders 2010

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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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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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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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(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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(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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(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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(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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(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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(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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(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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(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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(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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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")



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COAGULATION (DIC)

y Activation of the fibrinolytic mechanism aggravates thehemorrhagic diathesis



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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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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



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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



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COAGULATION (DIC)

y Could result from pathologic activation of the extrinsicand/or intrinsic pathways of coagulation or impairment of

clot-inhibiting influences



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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.



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COAGULATION (DIC)



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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



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COAGULATION (DIC)



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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



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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



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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



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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



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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



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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



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COAGULATION (DIC)


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End.

Documents

Bleeding Disorders 2010