DISORDERS OF

HEMOSTASIS

Hemostasis
Definition: The mechanisms that ensure prevention and
stoppage of bleeding.
1. Primary hemostasis:
vessel wall
platelets
von Willebrand factor
2. Coagulation
- coagulation factors
3. Fibrinolysis
- plasmin

 Disorders of hemostasis:
Disorders of primary hemostasis: muco-cutaneous
bleeding (petechiae, echymoses, epistaxis, gum
bleeding, etc)
Disorders of coagulation: profound hemorrhage
(hemarthrosis, hematomas, internal bleeding)
Disorders of fibrinolysis:
Hyperfibrinolysis bleeding
Hypofibrinolysis - thrombosis

 Primary hemostasis involves:

Vessel wall
Platelets
Von Willebrand factor

Vessel wall structure

Adventitia

Intima -endothelium

Media

Platelets

Platelets

Megakaryocyte

- Glycolipidic

membrane
- Membrane bound
glycoproteins:
- GPIb
- GP IIbIIIa
- Cytoplasmatic
granules:
- dense: ADP, STH
- alpha: vWF, PDGF

Platelet ultrastructure

Von Willebrand
factor

Von Willebrand factor is secreted by endothelia as

monomer but is functional only as multimer
Multimers are eventually degraded by the vWF
cleaving protease (ADAMTS13)
vWF circulates in a complex with coagulation factor
VIII (VIII:RAg)

intact
- suprafata
netrombogena surface
Normal Endoteliul
endothelium
smooth,
non-thrombogenic

Endoteliu

Colagen
Media - fibre
musculare

Adventitia

Vascular lesion
LEZIUNE VASCULARA
mechanical
mecanica
fizica
physical
chimica
chemical
biologica
biological

Endoteliu

Colagen
Media - fibre
musculare

Adventitia

Vasoconstriction
contraction
smooth
Vasoconstrictie
- cotractia of
fibrelor
muscle
fibers innetede
the intimal
layer medie
musculare
din tunica

Endoteliu

Colagen
Media - fibre
musculare
Adventitia

Platelet adhesion mediated

by GPI and vWF

Aderarea plachetara - mediata de

GPIb si vWF

GP
IIbIIIa

AA - TxA2

STH d
ADP

PDGF

GPIb

Endoteliu

vWF
Colagen

Media - fibre
musculare
Adventitia

Platele aggregation triggered by

Agregarea plachetara
humoral mediators and mediated
- declansata de mediatorii umorali plachetari
by GPIIbIIIa
and
Fbg si Fbg
- mediata de
GPIIbIIIa

GPIIbIIIa

Fbg
GPIb
GP
IIbIIIa

AA - TxA2

vWF

STH d
ADP

PDGF

GPIb

Endoteliu

vWF
Colagen

Media - fibre
musculare
Adventitia

Aggregating platelets

Platelet
thrombus
Tromb plachetar

Endoteliu

Colagen
Media - fibre
musculare
Adventitia

Platelet
thrombus
retraction
Retractia
trombului
plachetar

Endoteliu

Colagen
Media - fibre
musculare
Adventitia

 Laboratory tests that explore primary

hemostasis:
Bleeding time: <5 min
Platelet count: 150 - 400 X 109/l
Platelet functionality tests:
aggregation tests: ADP, thrombin, ristocetin

vWF assessment quantitative and

qualitative

 Coagulation
The process through which plasma is transformed
from liquid to solid.
Essentially it consists of transformation of soluble
fibrinogen in insoluble fibrin polymers under the catalytic
action of thrombin (F II).
Thrombin is obtained from the inactive form prothrombin
at the end of a chain of enzymatic reactions known as the
COAGULATION CASCADE involving several enzymes and
coenzymes known as the COGULATION FACTORS.
Most coagulation factors are produced in the liver, therefore
liver disorders have a profound impact on coagulation.

INSTRINSIC
PATHWAY
CALEA INTRINSECA
Factori de
contact:

CALEA EXTRINSECA
EXTRINSIC
PATHWAY

XI

XII
KGM
PK

FT
(III)

XIa
IXa
VIII
FP3
Ca++

IX

Xa
V
FP3
Ca++

AT III

II

IX

VIIa

VII

Prot C
Prot S
TRM

X
XIII

IIa
XIIIa

Fbg
(I)

MoFB

FBs

Fibrina
(FB)

Current opinion: 2 consecutive phases

- Initiation Production of a small quantity of thrombin, that
cannot activate fibrinogen, but can actiivate the other
coagulation factors (back activation)
- Propagation Exponential growth of the quantity of
FT
VII
thrombin fibrin production

XI
IX
FT-VIIa

Xa

IXa

X
IXa-VIIIa

VIII

Xa-Va

II

XIa

XIII

IIa
XIIIa

Fbg

FBs

Fibrina

 Coagulation testing
- routine tests PT, APTT, TT
- individual coagulation factor testing
APTT explores PT (QT)
TT- explores
intrinsic pathway explores
fibrin-formation
extrinsic
(18-20s)
(30-40s)
pathway (11-15s)

Deficit

prolonged

Isolated FVII
deficit

prolonged

F XII,XI,IX,VIII
deficit

prolonged

prolonged

normal

F X,V,II deficit, or
global deficit
Anticoagulants

prolonged

prolonged

prolonged

Fibrinogen
deficit or global
defect

 Fibrinolysis
The fibrin clot
lysis mediated
by plasmin
Laboratory tests
that explore
fibrinolysis
the diluted-blood
clot lysis time:
150-300 min
FDP D-dimers

Fbg
(I)

MoFB
PAI

FBs

Fibrina
(FB)

tPA
tPA

Plasminogen

Plasmina
Alpha2
plasmin
inhibitor

DISORDERS OF PRIMARY HEMOSTASIS

VESSEL WALL DISORDERS:

Rendu-Osler disease (teleangyectasia)

Pathogenesis: Increased VEGF production intimal

proliferation without media and adventitia catching
up results in thin arteriole and venule vessel walls
Autosomal dominant inheritance
Muco-cutaneous vascular dilatations
(teleangiectasias) that rupture, leading to chronic
bleeding and chronic iron deficiency
Treatment:

Iron supplementation oral iron usually not enough

Transfusions
Surgical hemostasis

Rendu-Osler Teleangyectasia

Immunologic and immuno-alergic

vasculitis:

Collagen diseases, chronic hepatitis,

lymphoproliferative disorders, idiopathic
Usually symetrical purpura with signs of
vascular inflammation + organ involvement

Vasculitic purpura

 Henoch-Schonlein
purpura
Usually affects children and
young adults
Symetric purpura + arthritis
+ abdominal pain + renal
impairment
Sometimes associated with
streptococcus infection
Treatment:
Usually spontaneous
remission
If not corticosteroids
Streptococcus
eradication

 PLATELET DISORDERS

Quantitative and Qualitative

Quantitative: Thrombocytopenias are
probably the most common causes of
pathological bleeding

Thrombocytopenia (<100,000/l)
Bleeding rarely occurs when platelets are >50,000/l
Spontaneous bleeding occurs at <20,000/l
Classification:
Central thrombocytopenia: megacaryocytes defect
appearing in:

aplastic anemia (rarely pure amegacaryocytosis)

acute and chronic leukemias
lymphomas
disseminated solid tumors
infection: tuberculosis

Peripheral thrombocytopenia:
Non-immune: sequestration (splenomegaly)
Immune:
Idiopathic thrombocytopenic purpura (ITP, chronic, acute)
Secondary autoimmune thrombocytopenia
Chronic ITP is more frequent in adults. Acute ITP occurs mostly in
children.

IDIOPATHIC THROMBOCYTOPENIC
PURPURA (ITP)
Definition: Thrombocytopenia
caused by immune,
autoantibody-mediated platelet
destruction
Etiology: unknown, as in most
autoimmune diseases
Pathogenesis:
IgG autoantibodies against
GPIIbIIIa.
platelet destruction occurs
mostly in splenic macrophages
There coexists a decresed
platelet production (antibody
attack on megakaryocytes?)

Anti platelet
antibody

Macrophage
GPIIbIIIa

FcR

Platelet

ITP - CLINICAL PICTURE: MUCO-CUTANEOUS BLEEDING

Petechiae
Echymoses
Epistaxis
Gum bleeding
No splenomegaly

 Laboratory features:
Plt <50,000, often <10,000/mm3
WBC, Hgb usually normal
Bone marrow: normal megacaryocytes,
sometimes megacaryocyte hyperplasia
Anti-platelet antibodies low specificity
and sensitivity
ANA, HIV, HCV, HBV, Helicobacter Pylori
should be negative

 Treatment:
Corticosteroids: Prednisone 1mg/kg 2mg/kg up
to 2-3 months
complete response in 20%, partial response in most
patients

If there is no significant response after

corticosteroids: splenectomy
complete response in 80% of patients

IVIG 400mg/kg 3-5 days temporary measure

Thrombopoietin receptor agonists: eltrombopag,
romiplostim

Prognosis: good, even in the minority of

patients in which splenectomy fails

THROMBOTIC THROMBOCYTOPENIC
PURPURA (TTP)
Definition. A rare disease defined by
reversible disseminated platelet
aggregation, bleeding, thrombosis, CNS
and renal disturbances
2 forms:
congenital (extremely rare)
acquired

 Pathogenesis:
Abnormal persistence of high molecular
weight von Willebrand factor multimers,
due to absence of vWF cleaving protease
(ADAMTS13)
Acquired form: antibodies against the vWF
cleaving protease
Excess FvW - Disseminated platelet clots
both thrombosis and bleeding may occur

Anticorpi anti-ADAMTS13

Multimer
vWF

Multimer
vWF

ADAMTS13
Monomer
vWF

Normal

ADAMTS13

ADAMTS13 - enzima de
clivare a vWF

ADAMTS13 - enzima de
clivare a vWF

TTP

 Clinical picture:

abrupt onset
mucocutaneous bleeding
pallor + jaundice
thrombosis: cerebral, cardiac, etc
transient neuro-psychiatric symptoms
renal failure

Laboratory features:
thrombocytopenia, sometimes severe
anemia, reticulocytosis, schisocytes
BUN, creatinine elevation

Schyzocytes

 Treatment:
Plasma exchange (PEX): plasmapheresis +
massive plasma transfusion
Corticosteroids, cyclophosphamide
Aspirin
Rituximab
Dialysis

Prognosis:
used to be dismal, 80% mortality
nowadays mortality <20%
sometimes debilitating sequelae, relapses

P = Plasma exchange

R4

R = Rituximab 700mg

R3

Plt

R2

P5

P4

P3
P1 P2

P9

R1

P6
P7 P8

VON WILLEBRANDS DISEASE

Etiology: Hereditary disease autosomal dominant
Clinical picture: muco-cutaneous bleeding especially
ENT
the symptom intensity tends to abate with age

Laboratory:

prolonged bleeding time, normal PT and APTT

Low levels of vWF (VIII:RAg)
Low ristocetin cofactor activity
Sometimes associated with low levels of coagulation factor
VIII (VIII:C)

Treatment:
plasma, cryoprecipitate transfusions
Factor VIII:C + vWF concentrate
Desmopressin

Classification of von Willebrand disease:

Type 1: Moderate vWF quantitative defect dominant
inheritance (70-80% of cases)
- associated with lower levels of VIII:C (but >10%)
- mild/medium hemorrhage
Type 2: Qualitative defect (normal VIIIR:Ag levels)
dominant inheritance medium/mild (20-25% of cases)
- 2A, 2B polimerization defect
- 2M defect of binding to platelets
- 2N defect of binding to VIII:C
Type 3: Severe quantitative defect recessive inheritance
(1-5% of cases)
- severe hemorrhage
- associated with low levels of VIII:C (5-10%)

THE HEMOPHILIAS (FVIII/IX deficit)

Etiology: hereditary X-linked diseases: both FVIII and
FIX genes are found on chromosome X women are
carriers, men are sick
Hemophilia A Factor VIII deficit (85%)
Hemophilia B Factor IX deficit (15%)

Clinical picture: deep bleeding:

Hemarthrosis (knee, shoulder, elbow, hip), hematomas,
hematuria
After minor/major surgery or trauma
3 clinical forms are described:
severe: spontaneous hemorrhage (VIII/IX - <1%)
medium : hemorrhage after minor trauma (VIII/IX 1-5%)
mild: hemorrhage after trauma and surgery (5-25%)

Severe hemophilia Knee hemarthrosis

Severe hemophilia muscle hematoma

Hemophilia Muscle hematoma

 Laboratory:
Prolonged APTT
Normal PT, TT, BT
Specific dosage of VIII/IX levels
Severe form: <1% residual factor
Moderate form: 1-5% residual factor
Mild form: 5-25% residual factor

 Treatment:
Imobilisation, bed rest
Painkillers
Substitution:
Should be given as soon as possible after event onset
Concentrates VIII and IX 20-40 units/kg single dose or
repeated if necessary at 12 hours (VIII) or at 24 hours (IX)
Desmopressin in medium/mild forms
Prophylactic treatment 20-40 units/kg 2-3 times/week
in severe forms practically transform severe form
patients into medium form patients

Kineto-physiotherapy

 Complications:
arthropathy various degrees of disability
chronic hepatitis (B,C), AIDS