Definitions
Coagulation
• The action or process of blood or liquid changing
to solid or semi-solid state.
Bleeding
• The release of blood from broken vessel, either
inside or outside the body.
Disorder of coagulation and bleeding
• Is a set of problems that disrupt the normal
physical functions of regulatory pathways of
bleeding and clotting.
Haemostasis.
Balance of maintaining bleeding and Coagulation.
Components of Normal Haemostasis
• Blood vessels
– Endothelial cells
– Sub-endothelial surface
• Platelets: primary haemostasis
– Platelet membrane
– Platelet granules
• Coagulation factors
• Fibrinolytic pathway
• Naturally occurring inhibitors of coagulation
The Endothelial Cell
Naturally Occurring Inhibitors: E.g.
Protein C Pathway
Coagulation Tests
•
•
•
•
•
Prothrombin time
Activate partial thromboplastin time
Thrombin time
Fibrinogen level
Tests for platelet disorders
–Platelet count
–Platelet aggregation test
–Skin bleeding time
Components of haemostasis

Blood vessel wall


Coagulation
factors
Platelets
Primary haemostasis
Secondary Haemostasis
Von Willebrand factor (VWF)
• This is synthesized by
endothelial cells and
megakaryocytes.
• Required for platelets
adhesion.
Coagulation system
Hoffman et al. Hematology: Basic Principles and Practice,
Fibrinolysis
• In fibrinolysis, a fibrin clot is broken to soluble
fragments which can be eliminated.
• Impaired fibrinolysis  thrombosis
• Excessive activation of fibrinolysis  bleeding
Regulation of Fibrinolysis
• Regulated by Plasminogen activator inhibitor
(PAI) and 2-antiplasmin
• Also regulated by TAFI (thrombin activated
fibrinolysis inhibitor)
Disorders of hemostasis
1. Disorders of primary hemostasis(abnormal platelet plug
formation at vascular injury site)
– Vessel wall disorders
– Platelet disorders
2. Disorders of secondary hemostasis (reduced thrombin
generation and fibrin clot formation)
– Disorders of clotting factors
– Fibrinogen disorders
3. Disorders of tertiary Hemostasis (premature degradation
of platelet or fibrin clot due to excessive fibrinolysis)
– Disorders of fibrinolysis
Disorders of primary hemostasis
Vessel wall abnormalities
Vascular endothelium:
–Inhibits platelet aggregation,
–Suppresses coagulation,
–Promotes fibrinolysis,
–Modulating vascular tone and permeability.
• Therefore, vascular abnormalities will lead
to either excessive bleeding of excessive
clot formation.
PLATELETS DISORDERTHROMBOCYTOPENIA
9
10 /L
• Normal count: 150-450 x
• Platelets remain in the circulation
for 8-10 days
–Thrombocytopenia is when platelet
9
count <150 x 10 /L
Platelets production and related
disorders
The pathophysiology
of thrombocytopenia
Thrombocytopenia Associated with HIV
Infection
Thrombocytopenia is common in HIV positive
patients.
Various causes of thrombocytopenia include:Reduced platelet production.
Accelerated platelet destruction
splenic sequestration, and
Rarely due to
Platelet consumption associated with
thrombotic thrombocytopenic purpura (TTP).
Medications,
Concurrent infections such as hepatitis C,
and
Hematologic malignancies
Nutritional Deficiencies and Alcohol-Induced
Thrombocytopenia
• Associated with megaloblastic anemia resulting
from vitamin B12 deficiency and folic acid.
• Alcoholics:
– liver cirrhosis with relative TPO(thrombopoietin)
deficiency, congestive splenomegaly, and/or
from folic acid deficiency.
– some patients(alcoholic), primarily from direct
marrow suppression.
Thrombocytopenia resulting from
accelerated platelet destruction

Immune



Autoimmune
alloimmune
Non-Immune

Thrombotic microangiopathies
Autoimmune thrombocytopenic purpura
Premature destruction of Platelets
 autoantibody or immune complex deposition on
their membranes.
Site of destruction:Reticulo-endothelial system
Spleen
Liver
bone marrow (less common).
Causes
Immune Thrombocytopenic Purpura
(ITP)
• Thrombocytopenia in which
apparent exogenous etiologic
factors are lacking and in which
diseases known to be associated
with secondary thrombocytopenia
have been excluded.
Incidence
• Annual incidence
– 5.5 per 100,000 persons when cutoff platelet
count <100 x 109/L
– 3.2 per 100,000 using a cut-off platelet
count <50 x 109/L.
• The annual incidence of ITP is about 3 to 8
cases per 100,000 children with a peak in the 2
to 5 year age group.
Pathophysiology
• Caused by platelet-specific autoantibodies
– bind to autologous platelets
– rapidly cleared from the circulation by the
mononuclear phagocyte system via
macrophage FcγRIIA receptors
predominantly in the spleen, liver and bone
marrow.
• Activation of components of complement on the
platelet surface are also demonstrated.
Clinical picture
Acute ITP:A history of infection preceding (within 3
weeks) the onset of bleeding.
Most common infections:Common childhood exanthema (rubeola and
rubella) and viral respiratory diseases.
Now varicella zoster virus and EBV are the
most frequently identifiable viruses,
although nonspecific viral infections still
predominate.
May also occur after vaccination.
The severity of ITP in infants is similar to that
in older children, but compared to older children,
a relatively small percentage of infants develop
• Severity and frequency of hemorrhagic
manifestations correlate with the platelet
count.
Bleeding after trauma without spontaneous
hemorrhage:- platelet counts >50,000/μl.
Spontaneous hemorrhages (ecchymoses and
petechiae):- 10,000 and 50,000/μl.
Hemorrhages with serious morbidity and
mortality:- platelet counts <10,000/μl
• Older patients(Age >60 years) have an
increased incidence of major, life-threatening
bleeding.
Common presenting symptoms in patients with ITP
<1
%
Laboratory findings
Blood:
Blood
Abnormalities in platelet size and morphology
(platelet anisocytosis) are common.
The platelets often are abnormally large (3 to 4
μm in diameter) and reveal more than normal
variation in size and shape.
Diagnosis
• Anemia, if present, is proportional to the
extent of blood loss and is usually normocytic
• “Evans syndrome”:Thrombocytopenia and Coomb’s positive
hemolytic anemia and have no other known
underlying etiology.
• Prolonged bleeding time.
• The results of tests of blood coagulation (PT,
aPTT) are normal.
Bone marrow Aspiration findings
Megakaryocytes usually are
↑in size
↑ or normal in number
“Smooth” forms with single nuclei, scanty cytoplasm
and relatively few granules are common
It results markedly accelerated platelet
production and the presence of many young forms.
Normoblastic hyperplasia may develop as a result of
blood loss.
The leukocytes are essentially normal with the
exception of occasional eosinophilia
BMA often not indicated. It is indicated in
1. Atypical clinical symptoms: Presence of
malaise, lymphadenopathy,
hepatosplenomegaly or other cytopenias.
2. Age:
1. age >60 years to rule out MDS
2. Pediatric age to rule out leukemia
3. Refractory ITP: If patients do not respond to
therapy, to exclude other hematological
disorders.
THROMBOTIC MICOANGIPATHIES
THROMBOTIC MICOANGIPATHIES
 Thrombotic microangiopathy refers to a combination of ;
1). Microangiopathic hemolytic anemia
2). Thrombocytopenia
3). Microvascular thrombosis, regardless of cause or specific
tissue involvement
4) HUS (Triad of Thrombocytopenia, renal failure, microangiopathy
hemolytic anaemia)
5) Secondary thrombotic microngiopathy
TTP
Pentad" of signs and symptoms:
• Thrombocytopenia
• Microangiopathic hemolytic anemia;
• Renal failure
• Neurologic abnormalities
• Fever
"
Classification
• Three distinct types of TTP are
recognized:
 Congenital TTP – severe deficiency of
ADAMTS13
 Idiopathic TTP – autoantibodies to
ADAMSTS13
 Non- idiopathic TTP- associated with
malignancy, drugs, pregnancy etc
PATHOPHYSIOLOGY
• Unregulated vWF dependent platelet
thrombosis appear to be the mechanism of
TTP.
• Pathologic hallmark: Microvascular
occlusion of terminal arteries and
capillaries by platelet and vWF rich
thrombus (having NO THROMBIN).
LABORATORY FEATURES
• Anemia (1/3 have Hb less than 6 g/dl )
• Elevated reticulocyte count
• Thrombocytopenia (half of patient have
platelets below 20,000/µL )
• Increased serum lactate dehydrogenase
level
• Decreased serum haptoglobin level
Congenital (inherited) TTP
• Congenital TTP - rarer than adult-onset TTP
• The first episode of hemolysis (red cell
breakdown) and thrombocytopenia usually
occurs during infancy or early childhood.
–jaundiced and pale
–complain of headache or abdominal pain
–Nervous system symptoms, fever and
kidney impairment can develop exactly like
the adult forms.
Secondary haemostatic disorders
• Clotting factor disorders
– Hereditary (Haemophilia A and B, VWD)
– Acquired ( eg Vit K def, Liver disease,
drugs interfering with vit K, DIC)
• Fibrinogen disorders
–Congenital
–Acquired
Clotting factors disorders
• Inherited deficiencies of coagulation factors:
– Hemophilia A (deficiency FVIII) and Hemophilia B
(deficiency FIX)
– Less common congenital deficiencies of prothrombin
(FII), FV, FVII, FX, or FXI or fibrinogen
• Acquired deficiencies of coagulation factors:
– Decreased synthesis from severe liver disease,
vitamin K deficiency, intake of drugs interfering with
vit K metabolism,
– Consumption from excessive activation in DIC,
– Accelerated clearance by paraproteins or amyloid,
autoantibodies which shorten half life or interfere
with activity
Fibrinogen disorders
• Congenital disorders of fibrinogen
– Low or absent levels fibrinogen (afibrinogenemia or
hypofibrinogenemia)
– Synthesis of dysfunctional fibrinogen
(dysfibrinogenemia)
• Acquired disorders of fibrinogen
– Decreased synthesis or production of abnormal
fibrinogen
– Increased fibrinogen consumption
– Inhibitor of fibrin polymerization (paraproteins,
autoantibodies esp in SLE)
– Elevated levels fibrin(ogen) degradation products
• Congenital or acquired deficiency of FXIII for
fibrin crosslinking (prevents premature breakdown)
Tertiary Haemostatic disorders
• It is the degradation of fibrin mesh
• Plasmin degrades fibrin & restores
blood vessel flow in damaged vessels
• Premature lysis of fibrin plug causes bleeding
• Primary hyperfibrinolysis (fibrinolysis in absence of
coagulation activation), causes;
– inherited deficiency of PAI-1 or a2-antiplasmin
(Inhibitors of plasminogen activators and plasmin)
– Severe liver disease
– Snakebites
• Systemic hyperfibrinolysis from coagulation activation
by tissue factor (cancer) or artificial surfaces
(cardiac assist devices)
• Localized hyperfibrinolysis from menorrhagia or
hematuria due to high concentrations of t-PA and uPA in genitourinary tract
Approach to patient with bleeding
• Key elements of history and physical:
– Unprovoked, unexpected, significant, recurrent bleeding
– History of prolonged or excessive bleeding with surgery, dental
procedures, menses, childbirth
– Timing of abnormal bleeding with challenges (immediate, within
hours, days later)
– Severity of bleeding (transfusion requirement)
– Symptoms of bruising, prolonged bleeding with cuts, nosebleeds,
gum and oral bleeding, GI bleeding, joint or muscle bleeding,
urinary tract bleeding, other bleeding
– Drug history (NSAIDs, aspirin, anticoagulants)
• Likely acquired or congenital?
– Symptoms since childhood, positive family history (pattern of
inheritance, X linked?)
– If new problem, consider possible triggers (new medication or
medical problem such as development of immune disorder, liver
disease)
• Formulate differential diagnosis
Clinical features
Laboratory workup of bleeding
disorders
• Complete blood count  anemia?
Thrombocytopenia?
• Ferritin for iron deficiency
• Blood group and antibody screen
• Renal, Liver, and thyroid function tests
• Prothrombin time (PT), activated partial
thromboplastin time (aPTT), thrombin clotting
time (TCT),
• Fibrinogen level
• Von Willebrand screening
• Platelet aggregation studies
Prothrombin time (PT)
• Normal -11-16 sec
• Measures the time for plasma to clot in
presence of Tissue Factor and Calcium
– Vit K dependent factors (II,VII,X)
– Extrinsic & intrinsic pathway
Causes of prolonged PT
–Oral anticoagulants
–Liver disease
–Vitamin K def (obstructive jaundice)
–DIC
–Factor 7 (isolated prolongation)
–Factor 2,5,10
Activated Partial Thromboplastin Time
• Measures time taken by
plasma to clot by activating
the intrinsic pathway.
– calcium
– Kaolin
• -activate the contactdependent Factor XII
– Cephalin
• substitutes for platelet
phospholipids
• Normal 26-40 secs.
Activated Partial Thromboplastin Time
• Tests for intrinsic pathway
– Deficiencies of all factors
except factor 7
– Inhibitors
– Heparin monitoring
– DIC
– Liver disease
– Massive transfusion
Thrombin time
• Time taken for the plasma to form clot on
addition of thrombin
• Normal 15-19 sec /within 2 sec of control
• Causes of prolongation
– Hypofibrinogenemia
– Dysfibrinogenemia
– FDPs (Fibrin deposition products)
– Heparin (RVV normal)
– Hypo/paraproteinemia
Platelet function tests
• If platelet count and initial screening
tests normal, consider von Willebrand
disease or platelet function defect
–Test for von Willebrand antigen, von
Willebrand factor Platelet aggregation
studies  light transmission
aggregometry in platelet rich plasma
–Flow cytometry to evaluate for
abnormal surface expression of platelet
glycoproteins
Categorization of bleeding disorders by PT and PTT results
Hoffman et al. Hematology: Basic Principles and Practice
REFERENCES
• Davidson’s principles of internal medicine,21st
edition.
• Harrisson’s,Manual of Medicine,19th Edition,Mc
Graw-Hill Education:New York,2016,p.
• Merck S. & Dohme C.,MSD Manual,Professional
version,Kenilworth:USA,2017;