THROMBOSIS

AND
DISORDERS
OF
HEMOSTASIS
 Hemostasis

l A series of reactions
designed for stoppage of
bleeding
l During hemostasis, three
phases occur in rapid
sequence
– Vascular spasms –
immediate vasoconstriction
in response to injury
– Platelet plug formation
– Coagulation (blood clotting)
 Blood Vessel Damage Vascular Phase
l Lasts about 30 mins
l Endothelial cells at the injury site
Smooth muscle in BV wall undergo changes:
contracts – Vascular Spasm – Contract and expose their
basement membrane to the
bloodstream
– Release chemical factors and local
hormones
BV diameter ¯ l ADP, tissue factor, and
prostacyclin
– Endothelial cell membranes
become sticky
Blood loss slows
Platelet Plug Formation
 Platelets
l Platelets are Flattened disk-like cell fragments
that are about 1µm by 4µm diameter.
l Their granules contain serotonin, Ca2+,
enzymes, ADP, and platelet-derived growth
factor (PDGF)
l Platelets function in the clotting mechanism by
forming a temporary plug that helps seal
breaks in blood vessels
l Platelets not involved in clotting are kept
inactive by NO and prostaglandin I2
Ultrastructure of platelets

Secretory granules
Diagrammatic Representation of the Platelet
 Platelet Plug Formation
l Platelets do not stick to each other or to the endothelial
lining of blood vessels
l Upon damage to blood vessel endothelium (which
exposes collagen) platelets:
– With the help of von Willebrand factor (VWF) adhere to
collagen
– Are stimulated by thromboxane A2
– Stick to exposed collagen fibers and form a platelet plug
– Release serotonin and ADP, which attract still more
platelets
l The platelet plug is limited to the immediate area of
injury by PGI2
 Coagulation

l A set of reactions in which blood is transformed

from a liquid to a gel
l Coagulation follows intrinsic and extrinsic
pathways
l The final three steps of this series of reactions are:
– Prothrombin activator is formed
– Prothrombin is converted into thrombin
– Thrombin catalyzes the joining of fibrinogen into a
fibrin mesh
BLOOD COAGULATION
 Coagulation Phase 1: Two Pathways to
Prothrombin Activator
lMay be initiated by either the intrinsic or
extrinsic pathway
– Triggered by tissue-damaging events
– Involves a series of procoagulants
– Each pathway cascades toward factor X
lOnce factor X has been activated, it complexes
with calcium ions, PF3, and factor V to form
prothrombin activator
Coagulation Cascade (Robbins)
Anti-coagulation
 Coagulation Phase 2:
Pathway to Thrombin
l Prothrombin activator catalyzes the
transformation of prothrombin to the
active enzyme thrombin
 Coagulation Phase 3: Common
Pathways to the Fibrin Mesh

l Thrombin catalyzes the polymerization of fibrinogen

into fibrin
l Insoluble fibrin strands form the structural basis of a
clot
l Fibrin causes plasma to become a gel-like trap
l Fibrin in the presence of calcium ions activates factor
XIII that:
– Cross-links fibrin
– Strengthens and stabilizes the clot
Polymerisation of fibrinogen
ULTRASTRUCTURE OF THROMBUS
ENZYME AMPLIFICATION
 Clot Retraction and Repair

lClot retraction – stabilization of the clot by

squeezing serum from the fibrin strands
lRepair
– Platelet-derived growth factor (PDGF)
stimulates rebuilding of blood vessel wall
– Fibroblasts form a connective tissue patch
– Stimulated by vascular endothelial growth
factor (VEGF), endothelial cells multiply and
restore the endothelial lining
 Factors Limiting Clot Growth
or Formation
lTwo homeostatic mechanisms prevent clots
from becoming large
– Swift removal of clotting factors
– Inhibition of activated clotting factors
Antithrombotic Attributes of Vascular
Endothelium
 Intrinsic Pathway of Blood Coagulation

l Clinical test to assess the functionality of this

pathway is the activated partial thromboplastin
time (aPTT)
– Kaolin and cephalin are added to the test plasma sample
– The normal range is ~30 – 50 seconds (varies slightly
depending on the laboratory)
– Prolongations in the aPTT are observed in deficiencies of
factor XII (or its cofactors), or factors XI, IX, VIII, X,
and V, or prothrombin (II).
– Used to test for common congenital hemophilias
(deficiencies in IX, VIII, or XI) and to monitor heparin
treatment
 Extrinsic Pathway of Blood Coagulation

l Clinical test to assess the functionality of this

pathway is the prothrombin time (PT)
– Lipidated tissue factor is added to test plasma sample
– The normal range is ~10-15 seconds (varies slightly
depending on the laboratory)
– Prolongations in the PT are observed in deficiencies of
factors VII, X, V, prothrombin (II), or fibrinogen (I).
– Used to test for the rare congenital deficiencies in these
factors: More often it is used to diagnose acquired
bleeding disorders resulting from vitamin K deficiency,
oral anticoagulants (e.g. warfarin), and liver disease
 Common Pathway of Blood Coagulation

l Tested clinically by the thrombin time (TT)

l In this test, thrombin is added to the plasma

– The normal range is ~10-15 seconds (varies slightly
depending on the laboratory)
– Prolongations in the TT are observed in congenital
fibrinogen deficiency or acquired fibrinogen deficiency
resulting from consumption of fibrinogen in DIC
(disseminated intravascular coagulation), or may occur
following treatment with fibrinolytic drugs
 NORMAL HAEMOSTATIC BALANCE

Naturally
occurring
Pro-coagulants anticoagulants
and platelets. and good
vascular flow

Thrombosis Bleeding
 Hemostasis Disorders:
Thrombus – a clot that develops and persists in
an unbroken blood vessel
− Thrombi can block circulation, resulting in tissue death
− Coronary thrombosis – thrombus in blood vessel of the
heart

Embolus – a thrombus freely floating in the

blood stream
−Pulmonary emboli can impair the ability of the body to
obtain oxygen
−Cerebral emboli can cause strokes
Thrombi & Emboli
l A thrombus is formed when
platelets begin to stick to the wall
of an intact blood vessel
– Platelets are often attracted to
arteriosclerotic plaques – where Above: Normal artery
endothelial and smooth muscle cells
Below: Same artery with a
contain lots of lipids. large thrombus (arrow)

l If the clot (thrombus) breaks off

and begins to drift in the
bloodstream, it is called an
embolus.
 VENOUS THROMBOSIS

l Swollen painful leg

Dr. Rudolph Virchow
1821-1902
 Case 1
l A 78-year-old white male is brought into the emergency
room with nausea, dyspnea, and a crushing substernal
chest pain that radiates to his left arm and jaw;
l The pain has lasted for about 30 minutes and is not
relieved with rest.
l One sublingual nitroglycerin tablet did not relieve his
pain.
l His history reveals a sedentary lifestyle, moderate
hypercholesterolemia, and obesity. The patient is also a
diabetic and smokes.
 Case 1

Labs: Elevated CK-MB; elevated troponin T

Case 1
Rupture of plaque in
atherosclerotic artery
 Endothelial Injury:
l Especially important in thrombus formation
in the heart and arterial circulation
 Causes of endothelial
injury:
l Myocardial infarction –formation of the thrombus
within the cardiac chambers
l Ulceration or rupture of plaque in atherosclerotic
arteries
l Traumatic injury
l Inflammation of the artery wall – vasculitis
(bacterial or autoimmunological)
l Cigarette smoke
l Hypercholesterolemia, homocystynuria
 Case 2
l A 61-year-old man without a contributory family history,but
with a history of slight diabetes and hypertension, experienced
chest discomfort and was admitted to a local hospital.
l On admission, he was in profound shock with orthopnea.
l Electrocardiography showed ST-segment elevation in leads
V1–4.
l Elevated creatine kinase (CK) at 1,800 IU/L
l Emergency coronary angiography demonstrated the occlusion
of the proximal left anterior descending coronary artery
(LAD).
 Case 2
l Eleven hours after starting thrombolytic therapy,
the patientexperienced the abrupt onset of severe
bilateral leg pain, from the groin down.
l Examination disclosed disappearance of both
femoral pulses and evidence of rapidly
progressing leg ischemia.
l Emergency aortography revealed a saddle
embolus at the aortic bifurcation.
Case 2
Alterations in Normal Blood Flow:
l Laminar flow
– Streamlined
– Outermost layer moving
slowest and center moving
fastest
– Cells do not contact with
endothelium

l Turbulent flow
– Interrupted
– Rate of flow exceeds
critical velocity
– Fluid passes a constriction,
sharp turn, rough surface
 Alterations in Normal Blood
Flow:
l Transformation from laminar blood flow to
turbulent flow contributes to formation of
countercurents and local pockets of stasis
l Disruption of laminar flow brings platelets
into contact with endothelium and damages
endothelial cells
 Alterations in Normal Blood
Flow:
l Artherosclerotic vascular constrictions are
common sources of turbulent flow and
thrombosis
l Aneurysms –abnormal aortic and arterial
dilations causes local stasis and turbulence
l Conjunction of atrial fibrillation and atrial
dilation results in profound stasis and
thrombus development.
 Case 3
l A 78-year-old man with paroxysmal atrial fibrillation and chronic
congestive heart failure was admitted to hospital due to global
aphasia and right-sided paralysis.
l His past medical history included a 6-year history of hypertension
and Parkinson’s disease, a 2-year history of chronic renal failure.
l On admission, his blood pressure was 160/101 mmHg, and his
pulse was 103 beats/min and irregular. No abnormal sounds were
heard on chest auscultation.
l Brain CT showed early ischemic changes in the left cerebrum.
l On carotid ultrasonography, small plaques were noted in the
bifurcations bilaterally.
 Case 3

left atrial appendicular thrombus

 Case 4
l 63 years old male was hospitalized in general surgery department
for planed partial gastrectomy due to gastric cancer which had been
diagnosed a week before.
l Two days after surgical procedure he developed sudden swelling
and pain in his right leg and 38C fever.
l On Doppler ultrasonographic evaluation in his lower extremity there
was acute and early subacute thrombosis in popliteal and distal
crural veins, and chronic thrombosis in the superficial femoral vein,
and insufficiency in the great saphenous vein below the knee level.
 Case 4
l Soon after onset of symptoms he developed a non-
productive cough, severe pain localized to the right
hemithorax, and hemoptysis.
l arterial blood pH was 7.46, pCO2: 32.6 mmHg and pO2 :
81.0 mmHg with oxygen saturation of 97.4%.
l D-dimer level on admission was 1,538 ng/mL (Normal
range: 0-500 ng/mL).
 Case 4

l In pulmonary tomography and angiography, the left main pulmonary artery,

superior lobe and apicoposterior segment branches, lingual, lower lobe and
lower lobe posterior-lateral basal segment branches, on right the lower lobe
superior, posterior and lateral basal segmental arteries revealed filling defects
relevant to pulmonary venous thromboembolism.
 Case 5
l A 63-year-old woman was admitted following a flight from
Auckland on account of dyspnoea and pleuritic chest pain on
alighting from the aircraft.
l She had experienced swelling of her legs during the flight. On
examination she was cyanosed, blood pressure 90/60 mmHg, the
heart rate was 110 per min, the jugular venous pressure was
elevated and the heart sounds were normal.
l Bilateral basal crepitationsand pitting oedema of the feet were
present.
l Soon after arrival at the hospital she became asystolic, and
although initial resuscitation was successful she died a few hours
later.
l The diagnosis of pulmonary embolism from thrombosis in the calf
veins was made at post-mortem.
 Case 6
l 9yo male at presents for eval for psych
admission for acute psychosis.
l Disorganized behavior, non-communicative
except occasional screaming fits.
l Associated symptoms headache, high
fevers, occasional watery stools.
l Head CT with contrast notes lateral venous
sinus thrombosis.
 Inherited hypercoagulability
states
l Antithrombin deficiency
l Abnormalities in protein C and protein S system
- protein C deficiency
- protein S deficiency
- abnormal thrombomodulin
● Elevated level of prothrombin in plasma
l Resistance to activated protein C (FV Leiden, FV Cambridge)
Inherited Activated Protein C Resistance
“Factor V Leiden”

• Point mutation in the Factor V gene - Factor V

Leiden

• Prevalence in Western Populations ~2-5%

• Rare in Eastern/Oriental populations

• Autosomal dominant trait

• Responsible for ~60% of familial thrombosis

 Factor V Leiden
Factor Va

Arg 306 Arg 506 Arg 1765

Arginine Glutamine
CGA CAA
Result: Factor Va resistant to APC cleavage

Coagulation cofactor activity continues

 Prothrombin Gene Mutation
• Second most common hereditary risk
factor for venous thrombosis
• Present in 2% of Caucasian population
• Caused by a point mutation (G20210A) in
the prothrombin gene
 Prothrombin G20210A Mutation

l A G-to-A substitution in nucleotide position 20210 is

responsible for a factor II polymorphism
l The mutation causes a 30% increase in prothrombin
levels.
 Antithrombin III Deficiency

l Inhibits coagulation by irreversibly binding the

thrombogenic proteins thrombin (IIa), IXa, Xa, XIa
and XIIa
l Antithrombin’s binding reaction is amplified 1000-
fold by heparin, which binds to antithrombin to cause
a conformational change which more avidly binds
thrombin and the other serine proteases
 Protein C Deficiency

l Protein C is a vitamin K dependent glycoprotein produced in the

liver
l In the activation of protein C, thrombin binds to
thrombomodulin, a structural protein on the endothelial cell
surface
l This complex then converts protein C to activated protein C
(APC), which degrades factors Va and VIIIa, limiting thrombin
production
l For protein C to bind, cleave and degrade factors Va and VIIIa,
protein S must be available
l Protein C deficiency, whether inherited or acquired, may cause
thrombosis when levels drop to 50% or below
l Protein C deficiency also occurs with surgery, trauma,
pregnancy, OCP, liver or renal failure, DIC,or warfarin
 Protein S Deficiency

l Protein S is an essential cofactor in the protein C

pathway
l Protein S exists in a free and bound state
l 60-70% of protein S circulates bound to C4b binding
protein
l The remaining protein S, called free PS, is the
functionally active form of protein S
l Inherited PS deficiency is an autosomal dominant
disorder, causing thrombosis when levels drop to
50% or lower
 Case 7
l A 54-year-old woman with 20 years of SLE
diagnosis was admitted because of abdominal
pain.
l The high titer of anti-cardiolipin autoantibodies
was found in labs.
l The patient had no prior abdominal complications
but she had an active disease with twenty-four
spontaneous abortions and five strokes.
l The patient was chronically treated with warfarin,
but did not manage a therapeutic range.
 Case 7
l On admission, the patient complained of abdominal
pain, nausea and weakness, temperature of 37.3 was
measured, a blood pressure of 125/85 mmHg, regular
heart rate of 110 per minute and 16 breaths per minute.

l Physical examination revealed tender abdomen,

enlarged spleen 17 cm and enlarged liver 18 cm.

l Abdominal CT angiography revealed splenic vein,

portal vein and superior mesenteric vein thrombosis,
hepatosplenomegaly and multiple spleen infarcts.
 Antiphospholipid Antibody
Syndrome
l Antiphospholipid syndrome (APS) is a disorder that
manifests clinically as recurrent venous or arterial
thrombosis and/or fetal loss.
l Characteristic laboratory abnormalities in APS include
persistently elevated levels of antibodies directed against
membrane anionic phospholipids (ie, anticardiolipin [aCL]
antibody, antiphosphatidylserine) or their associated
plasma proteins, predominantly beta-2 glycoprotein I
(apolipoprotein H); or evidence of a circulating
anticoagulant.
 Antiphospholipid Antibody
Syndrome
l Antiphospholipid antibodies associated with vaso-
occlusive events without any underlying disease
process is termed the primary antiphospholipid
antibody syndrome (PAPS).

l The presence of antiphospholipid antibodies and a

vaso-occlusive event superimposed on an
underlying disease, such as SLE or malignancy, is
a secondary antiphospholipid antibody syndrome.
 APS Pathophysiology
Possible mechanisms by which antiphospholipid antibodies may induce
thrombotic events include the following:
l Antiphospholipid antibodies may combine with platelet membrane
phospholipids, resulting in increased platelet adhesion and aggregation.
l Antiphospholipid antibodies may combine with the endothelial cell
membrane phospholipids and induce endothelial cell damage, impaired
prostacyclin production, increased platelet adhesion, and aggregation.
l Antiphospholipid antibodies can stimulate production of antibodies
against coagulation factors, including prothrombin, protein C, protein
S, and annexins
l b2-GPI and oxidized low-density lipoprotein (oxLDL) complexes may
be bound up by antiphospholipid antibodies, cleared by macrophages,
and, thus, promote accelerated development of atherosclerosis in
autoimmune patients.
LIVEDO RETICULARIS
 BLEEDING DISORDERS or
HEMORRHAGIC DIATHESES
Excessive bleeding may result from:
l Increased fragility of blood vessels
l Platelet deficiency or dysfunction
l Derangements in coagulation mechanism
l Combintion of more than one reasons
 Bleeding disorders caused by
vessel wall abnormalities
l Relatively common
l Usually induce small hemorrhages in the
skin or mucous membranes (particularly the
gingivae)
l Tests of coagulation (platelet count,
bleeding time, PT, PTT) are usually normal
 Case 7
l A 18-month-old white female is brought to the pediatric clinic
because of apathy and anorexia.
l She is the daughter of an unemployed poor urban couple and has
never before seen a pediatrician or taken an medication.
l Her parents report a diet of an unsupplemented cow's milk
l PE: Weakness; hyperkeratosis and hemorrhagic perifolliculitis
of kin of lower extremities and forearms; splinter hemorrhages in
nail beds of hands; bleeding gums; petechiae seen over nasal and
oral mucosa.
l Labs:
– microcytic, hypochromic anernia
– prolonged bleeding time
– levels of ascorbic acid low
Case 7
 Case 8
l A 9-year-old boy is brought to the emergency room with pain,
inability to move his left shoulder, and flattening of the normal
rounded shoulder contour (shoulder dislocation) that occurred when
he tried to hit a ball with his bat at a local baseball field.
l He has dislocated his left shoulder nine times before and his right
shoulder three times before. He also has a history of easy bruising.
l Hyperelastic skin; hyperextensibility of joints; left shoulder
dislocated; multiple bruises over skin.
l Labs Clotting profile normal.
l Skin biopsy: co1lagen fibrils of dermis of skin larger than normal and
irregular in outline on electron microscopy.
 Ehlers-Danlos Syndrome
l Ehlers-Danlos syndrome (EDS) is the name
given to a group of more than 10 different
inherited disorders;
l all involve a genetic defect in collagen and
connective-tissue synthesis and structure.
l Ehlers-Danlos syndrome can affect the skin,
joints, and blood vessels.
l Is characterises by joint hypermobility,
cutaneous fragility, and hyperextensibility
 Ehlers-Danlos Syndrome
l The collagen defect has been identified in only 6 of the 11
types of Ehlers-Danlos syndrome.
l Type IV is characterized by a decreased amount of type III
collagen.
l Types V and VI are characterized by deficiencies in
hydroxylase and lysyl oxidase,
l Type VII has an amino-terminal procollagen peptidase
deficiency.
l Type IX has abnormal copper metabolism.
l Type X has nonfunctioning plasma fibronectin.
 Case 9
l An 8-year-old white male presents with an erythematous
skin rash over the buttocks and legs coupled with joint
pains, abdominal pain and hematuria.
l Three days before he had complained of cough, low-grade
fever, and sore throat,
l He has a history of allergy to dust and pollen.
l PE hypertension, palpable purpuric skin lesions over
buttocks and legs; painful restriction of knee and ankle
joint movement with swelling.
l Labs: normal platelet count; normal coagulation tests;
increased ESR; increased BUN and serum creatinine;
RBCs and RBC casts on urinary sediment.
Case 9
 Case 9
l Gross Pathology: Necrotizing vasculitis of
kidneys and lungs.
l Micro Pathology: Renal biopsy shows focal
and segmental glomerulonephritis with
crescents (mesangioproliferative);
mesangial IgA deposits on
immunofluorescence
 Henoch-Schonlein Purpura
l Henoch-Schoenlein purpura is an acute immunoglobulin A
(IgA)–mediated vasculitis that primarily affects children.
l The dominant clinical features of Henoch-Schoenlein purpura
include cutaneous purpura, arthritis, abdominal pain, GI bleeding,
orchitis, and nephritis.
l Is characterised by increased serum IgA concentrations, IgA-
containing circulating immune complexes, and IgA deposition in
vessel walls and renal mesangium.
l IgA aggregates or IgA complexes with complement deposited in
target organs, resulting in elaboration of inflammatory mediators,
including vascular prostaglandins such as prostacyclin, may play
a central role in the pathogenesis of Henoch-Schoenlein purpura
vasculitis.
 Bleeding disorders caused by
vessel wall abnormalities
l Induced by infection – vasculitis caused by
diplococcus menigitidis (meningococceal
septicemia)
l Result of deposition of immune complexes in the
vessel walls (Schonlein –Henoch purpura,
disorders induced by drugs)
l Induced by impaired formation of collagenous
support of vessels walls (Ehlers-Danlos syndrome,
excessive corticosteroids levels, vitamin C
deficiency)
 Bleeding disorders related to
reduced platelet number
l Condition known as Trombocytopenia
l Platelet count normally range between 150,000
and 300,000/mm3
l Spontaneous bleeding does not occur until the
platelents count fall below 30,000/mm3
l Characterized by bleeding from small vessels of
the skin and mucous membranes (petechie)
l Prolonged bleeding time
l Normal PT and PTT
 Common causes of
Trombocytopenia:
l Decrased production of platelets
l Decrased platelet survival
l Sequestration of platelets
l Dilutional trombocytopenia
 Case 10

l A 5-year-old white female is brought to her pediatrician because of

fever, marked weakness, pallor: bone pain, and bleeding from her
nose (epistaxis).
l She has a history of progressively increasing fatigability and
recurrent infections over the past few months,
l PE: fever; marked pallor; epistaxis; ecchymotic patches over skin;
light hepatosplenomegaly with nontender lymphadenopathy.
l Labs: normocytic, norrnochromic anemia; absolute lymphocytosis
with excess blasts (> 30%) and neutropenia;
l Thrombocytopenia (10.000/mcl).
 Case 10
l neoplastic infiltration of lymph nodes,
spleen, liver, and bone marrow with loss of
normal architecture.
l bone marrow: distorted architecture
secondary to pace-occupying lesions with
lymphoblastic infiltration; Iymphoblasts
with inconspicuous nucleoli, condensed
chromatin, and scant cytoplasm.
Decrased production of platelets

l Aplastic anemia
l Neoplasmatic infiltration of the bone
marrow (leukemia, metastases)
l B12 or folic acid deficiency (impaired
synthesis of DNA)
 Case 11
l A 31 year-old white female is brought to the emergency
room with a skin rash and severe epistaxis.
l The patient had a URI consisting of a severr cough and a
runny nose 10 days before the onset of her symptoms.
l She has no prior history of prolonged bleeding following
minimal trauma.
l PE: Mucosal petochiae; epistaxis ; hemorrhagic bullae in
buccal mucosa; spleen enlarged.
l Labs: low platelet count (10,000); RBCs and WBCs
normal.
l Prolonged bleeding time; normal PTT; normal PT.
 Idiopathic Thrombocytopenic Purpura
l Idiopathic thrombocytopenic purpura (ITP), also known as
primary immune thrombocytopenic purpura and autoimmune
thrombocytopenic purpura, is defined as isolated
thrombocytopenia with normal bone marrow and the absence of
other causes of thrombocytopenia.

l ITP is primarily a disease of increased peripheral platelet

destruction, with most patients having antibodies to specific
platelet membrane glycoproteins.

l Acute ITP often follows an acute infection and has a spontaneous

resolution within 2 months. Chronic ITP persists longer than 6
months without a specific cause.
 Decreased platelet survival

l Platelet destruction is caused by circulating

platelet auto-antibody
l Idiopathic trombocytopenic purpura (ITP)
l Drug induced thrombocytopenia
l HIV-associated thrombocytopenia
l Mechanical injury to platelets
(microangiopathic conditions)
 Case 12
l A 67-year-old woman came to the emergency department with
a chief complaint of swelling of both lower extremities,
abnormal coloration of her toes, and inability to walk for the
last day.
l She had undergone coronary artery bypass graft surgery 10
days earlier. Her postoperative course was benign, and she was
discharged on the fifth postoperative day.
l She had received unfractionated heparin during surgery to keep
the activated clotting time above 300 sec, and during the
postoperative period she received heparin 5,000 IU
subcutaneously twice daily.
l At discharge, her hemoglobin and hematocrit were 12.8 g/dL
(128 g/L) and 38% (0.38), respectively, and her platelet count
was 172,000/µmL (172 x 109/L).
 Case 12
l When examined at the emergency department, she was
alert and oriented. The toes on both feet were tender and
cyanotic. Both lower extremities were warm to touch, and
the posterior tibial and dorsalis pedis pulses were feeble,
but present.
l During hospitalization, her toes and the planter aspect of
the right foot became ischemic.
l Noninvasive venous studies of both lower extremities
showed extensive deep venous thrombosis bilaterally.
l Her hemoglobin and hematocrit were 9.4 g/dL (94 g/L)
and 28% (0.28), respectively, and her platelet count was
39,000/µmL (39 x 109/L).
Heparin induced thrombocytopenia
•Antibody against PF4-heparin
complex causes inactivation
and destruction of platelets
•Autoantibody binds platelets
to each other via interaction of
PF4 receptor and Fc-receptors
•Autoantibody IgG may bind to
endothelial cell bound heparin-
PF4 complex and cause
vascular damage
•Vascular damage and platelet
activation may provoke
thrombus formation
 Bleeding disorders related
to defective platelet
functions

l Defects of adhesion
l Defects of aggregation
l Disorders of platelet secretion
Bernard – Soulier syndrome:

•Autosomal recessive
condition
•Deficiency of platelet
membrane – bound
glycoprotein complex Ib
(receptor for von Willebrand
complex)
•Results in defective platelets
adhesion
Glanzmann’s thrombastenia
l Autosomal recesive
trait
l Deficiency of
glycoprotein IIb –IIIa
l Bleeding due to
defective platelet
aggregation
 Case 13

l A 17-year-old male is brought to the emergency room

because of weakness and the spontaneous appearance of
painful swelling of both knee joints as well as black, tarry
stool (GI bleeding).
l The child has a history of prolonged bleeding following
minor injuries.
l His maternal uncle died of a "bleeding disorder”.
l PE: pallor; swollen erythematous , tender knee joints with
blood accumulation in synovial capsule (hemarthrosis);
numerous bruises seen at areas of minimal repeated
trauma.
l Labs: Bleeding time and PT normal; prolonged PTT;
reduced levels of factor VIII on immunoassay.
Case 13
 Types of bleeding related to
derangements in coagulation mechanism

l Hemophilia A (factor VIII deficiency)

l Hemophilia B (factor IX deficiency)

l Hemophilia C – mild type, (factor XI deficiency)

l von Willebrand Disease (vWD)

l Other
 Hemophilias A and B

l Hemophilias A and B are cause by deficiencies in

factors VIII or IX, respectively

l Hemophilia A affects: 20.6 per 100,000 males

– Severe: 50-60%

l Hemophilia B affects: 5.3 per 100,000 males

– Severe: 44%

l Inherited as a recessive X-linked trait (Mom would be

an unaffected carrier)

l ~30 % of cases of hemophilia are new mutations

 VIII concentration and symptoms
Concentration, g/l Symptoms

100 – 50

50 - 30 Intensive and long lasting

bleeding after big trauma
30 – 5 Long bleeding after surgery and
minor trauma
5–1 Intensive/long bleeding after
minor trauma
<1 Spontaneous bleeding
Types of bleeds in hemophilia

l Joint bleeding - hemarthrosis

l Muscle hemorrhage
l Soft tissue
l Life threatening-bleeding
l Other
 Hemophilic Arthropathy
l As blood is catabolized, it is absorbed by
synovium
l Iron is toxic to cells – synovial cells
disintegrate releasing lysosomes which
destroy cartilage and inflame synovium
l Hypertrophic, hypervascular synovium
l Chondrocytes also affected
l FIBROSIS
Acute and Chronic Hemophilic Arthropathy
 Case 14
l A 52-year-old man gave a lifelong history of easy
bruising and excessive bleeding following tooth
extractions.
l After taking aspirin, he developed severe
nosebleeds. Family history was remarkable for
heavy vaginal bleeding in his mother and sister.
l Labs: Prolonged bleeding time; moderately
prolonged PTT; quantitative assay for factor VIII
reduced; low von Willebrand‘s factor (vWF)
antigen levels; low vWF activity.
 Von Willebrand’s Disease
l Most common inherited disorder
l Usually autosomal dominant
l Caused by mutation in vWF gene
l Split into several subgroups
l May be quantitative or qualitative defect
Role of vWF
l Multimeric glycoprotein
secreted by vascular
endothelium and
megakaryocytes
l Carries and stabilises
Factor VIII in plasma
l Mediates adhesion of
platelets to damaged
endothelium
 Laboratory Diagnosis
lAPTT may be prolonged, PT normal
lBleeding time may be prolonged
lF VIII and vWF levels usually reduced
lDefective Platelet Aggregation
 Types of
von Willebrand Disease

l Type I: quantitative - normal multimers but

decreased amounts
l Type 2: qualitative abnormality in VWF
– 2A: absence of (the hemostatically most
effective) large multimers of VWF
– 2B: the large multimers of VWF are abnormal,
having a heightened affinity for platelets

l Type 3: severe form of VWD- extremely low

levels of VWF and FVIII
 VON WILLEBRAND DISEASE
l TYPE I IS MOST COMMON.
– REDUCED QUANTITY OF CIRCULATING
VON WILLEBRAND FACTOR (vWF)
– SECONDARY DECREASE IN FACTOR
VIII BECAUSE vWF STABILIZES
FACTOR VIII
– APPROXIMATELY 70% OF ALL CASES
OF VON WILLEBRAND DISEASE
– RELATIVELY MILD