BLEEDING DISORDERS: Hemorrhagic Diatheses

Common Tests
Hemostasis
Greek haimostasis
from haimo (blood) + -stasis (standing still)
Definition
1 : stoppage of of blood flow
2 : arrest of bleeding (as by a hemostatic agent)
Results from well regulated processes that maintain blood in
fluid, clot free state in normal vessels while inducing rapid
formation of a localized plug in the site of injury
Has normal general sequence of events

Components of Hemostasis
1. Vascular intima
2. Cellular components Platelets
Principal Hereditary and Acquired Bleeding Disorders
3. Coagulation pathway Associated with Vascular Abnormalities
4. Fibrinolytic system

Vascular Intima
Innermost vascular lining
Endothelial cells
Supporting the endothelial cells
Internal lamina
- elastin
- collagen
Subendothelial Connective Tissues
Veins
- Collagen and fibroblast
Arterioles
- Collagen, fibroblast &
smooth muscles

Platelet Function Bleeding Related to Platelet Number: Thrombocytopenia

1. Adhesion
Platelets roll and cling to non-platelet surfaces
2. Aggregation
Platelets cling to each other
3. Secretion
Platelets discharge the contents of their granules

Types of hemostasis 1. Chronic Immune Thrombocytopenic Purpurs (ITP)

2. Thrombotic Thrombocytopenic Purpura

Bleeding Related to Defective Platelet Functions

Hemorrhagic Diathesis Related to

Abnormalities in Clotting Factors
Coagulation Pathway
Phases:
Phase 1: Activation of Factor X
Phase 2: Thrombin Formation
Phase 3: Fibrinogen

Stage 1:Vasoconstriction & Platelet adhesion

Stage II: Platelet aggregation
Stage III: Reinforcement of platelet plug and fibrin
Idiopathic Thrombocytopenic Purpura
Chronic Immune Thrombocytopenic Purpura (ITP)
Incidence: 3.2 to 6.6/ 100,000/ year
Mostly between 20 and 50 years old (<40 yo)
Female: Male Ration of 2-3:1
Highest incidence in Women 20-40 yo
Begins insidiously, bleeding into skin and mucosal
surfaces.
Pathogenesis:
Autoantibodies to platelets membrane
glycoproteins
Idiopathic Thrombocytopenic Purpura
Diagnosis:
1. Clinical Presentation
1. Bleeding signs and symptoms, in an otherwise
normal Complete Blood Count (CBC)
2. Sudden development of bleeding symptoms
3. No family history of hemorrhagic abnormalities
2. Physical Examination
-purpura. Petechiae, echymosis
Morphology:
PBS: Thrombocytopenia, Enlarged Platelets with
normal in morphology
Bone Marrow: Megakaryocytic hyperplasia, Larger
megakaryocytes
Spleen: normal in size, Congestion of sinusoids,
Increase number of megakaryocytes
Acute Idiopathic Thrombocytopenic Purpura
Incidence : 4/100,00 children
Peak frequency between 2 and 5 years of age
No sex predilection
Etiology: Follows a viral illness(1 - 3 wks after
infection)
Clinical Picture Of Acute and Chronic ITP
Immunologic Drug-Induced Thrombocytopenia
Mechanisms:
1. Quinidine/Quinine-Induced Thrombocytopenia
2. Induction of Hapten-dependent antibodies
3. Drug-induced autoantibodies
4. Heparin-induced thrombocytopenia
Quinidine/Quinine-Induced Thrombocytopenia
Quinine/Quinidine
Induces Antibody Production
Drug combines with the antibodies
Antibodies Fab portion bind to the GP Ib/IX or GP
IIb/IIIa leading to platelet fragmentation and
thrombocytopenia
Hapten-dependent antibodies
(Penicillin & Penicillin Derivatives)
Antibody
Drug bound to Protein Molecules
Drug-induced Autoantibodies
Procainamide, Gold Salts and Levodopa
Drug stimulate the formation of antibodies against
Platelet surface antigen
Exact mechanism unknown
Thrombotic Thrombocytopenic Purpura
Referred to as MOSCHCOWITZ SYNDROME
Common in women 30 to 40 years old
Triad/Pentad
1. Microangiopathic hemolytic anemia
2. Thrombocytopenia
3. Neurologic disorders
4. Fever and renal dysfuction
Hyaline thrombi composed of platelet and VWF are
deposited in end arterioles
Causes and Associations
1. Deficiency in plasma enzyme ADAMTS 13
Degrades very HMW multimers of von Willebrand
factor (wWF) accumulate promote platelet
activation and aggregation
2. Hemolytic Uremic Syndrome (HUS)
Epidemic
- strongly associated with infectious gastroenteritis
due to E.coli strain O157:H7 Alter endothelial cell
function platelet activation and aggregation
Non-epidemic
- Associated with defects in complement factor H,
membrane cofactor protein (CD 46) or factor I
activation of alternative complement pathways
3. Miscellaneous: Drugs, Radiation, Infections etc
Bernard Soulier Syndrome (Giant Platelet Syndrome) Disorder of Secretion
Rare autosomal recessive disorder STORAGE POOL DISEASES
Deficiency of Glycoprotein (GP) Ib/IX/V complex
- 1b (von Willebrand receptor) Dense Granules Deficiencies
Usually manifested in childhood and infancy Bleeding is usually mild and limited to easy
Lack binding site for vWF inability of platelet to bruisability
adhere to exposed subendothelium Affects the results of platelet aggregation tests
Hermansky Pudlak
Treatment: Chediak Higashi
No specific treatment Wiskott-Aldrich
Transfusion is the treatment of choice
Other treatments: Granule Deficiency
- Desmopressin acetate (DDAVP) Gray Platelet Syndrome
- Recombinant Factor VVa

Thrombocytopenia Dense Granules Deficiencies

- 40,000/cumm to near nornmal Addition of arachidonic acid fails to induce an
PBS: Enlarged/ GiantPlatelets aggregation response
- about 5 to 8 um diameter
Epinephrine and Low dose ADP induce a primary
EM: Cytoplasmic vacuoles and membrane complexes
wave of aggregation; secondary wave of aggregation
is missing.
Laboratory findings:
Collagen: Aggregation pattern due to lack of ADP
1. Prolonged bleeding time
secretion
2. Normal or decreased platelet count Low concentration results to decreased or low
3. Giant platelets aggregation response
4. Abnormal adhesion test High concentration results to near normal aggregation
5. Abnormal aggregation with ristocetin; normal response
aggregation patterns with ADP, epinephrine,
Hermansky Pudlak Syndrome
collagen and arachidonic acid
Autosomal recessive disorder
Chromosomal aberation in Chromosome 19
Glanzmann Thrombasthenia
Morphologic Disorder
Autosomal recessive disorder
1. Tyrosinase positive oculocutaneous albinism
First described by Dr. Eduard Glanzmann in 1918
2. Defective lysosomal function
Manifest clinically in the neonatal period or infancy
3. Ceroid-like deposition in the cells of the
platelet glycoprotein IIb/IIIa complex is either
reticuloendothelial system
deficient or present but dysfunctional
4. Profound platelet dense () granule deficiency
GP IIb/IIIa receptor for fibrinogen
Swiss Cheese Platelet
leads to defective platelet aggregation and
turtousity of the surface connecting tubular system
subsequent bleeding
Genetic Disorders: Granule Deficiency/Gray Platelet Syndrome
mutations involving IIb 3 genes in chromosome 17 Rare, autosomal recessive disorder
Clinical Presentation: First describe in 1971
Severe and disabling hemorrhage Diagnosis :
- epistaxis, ecchymoses, hemarthrosis, subcutaneous
hematoma, menorrhagia and gastrointestinal and urinary tract
Lifelong mild bleeding tendencies,
hemorrhage Fibrosis of the marrow
Requires repeated transfusions Large platelets gray appearance
Electron Microscopy
Glanzmann Thrombasthenia No Granules or small Granule with VWF and
fibrinogen
Prolonged Bleeding Time
Contain Vacuoles, membrane contain P-selectin (CD 62)
Normal platelet count and morphology and GP IIb/IIIa
Poor Clot retraction Plasma Levels
Lack of platelet aggregation response to all activating - Increased PF4 and -thromboglobulin
agents (ADP, Collagen, Thrombin and Epinephrine
Normal aggregation response to rest
Congenital Hemorrhagic Disorders Hemophilias (Factor Deficiencies)
Presents with repeated hemorrhages that maybe Ranked 2nd to VWD in prevalence among congenital
spontaneous or follow minor injury or maybe seen in bleeding disorders
unexpected locations Occur in 1 in 10,000 individuals
Common congenital deficiencies: Hemophilia A : Factor VIII deficiency - 85% of cases
1. Von Willebrand Hemophilia B : Factor IX deficiency -14% of cases
Hemophilia C : Factor XI or one of the other factors -1%
2. Factor VIII and IX
3. Rarely Fibrinogen, Factors V, VII, X, XI and XIII

Von Willebrand Disease (VWD)

First described by Erik von Willebrand
Affects 1% of population
VWF is synthesized in endothelial cells,
megakaryocytes ; stored in endothelial cells, Weibel-
Palade bodies and alpha granules of platelets
VWF levels are lowest in group O blood groups
4 Functional Domain of Von Willebrand Monomers
that binds:
Factor VIII
Collagen Factor Deficiency DIAGNOSIS
Platelet Glycoproteins Ib/V/IX
Platelet Glycoproteins IIb/IIIa
Functions:
Serves as the Factor VIII carrier molecule
Mediate platelet adhesion to the subendothelial
collagen in capillaries and arterioles

PATHOPHYSIOLOGY
Results to impaired primary hemostasis due to
impaired platelet adhesion and platelet aggregation
Caused by both quantitative and structural
abnormality of Von Willebrand Factor (VWF:R)
Severe quantitative VWF deficiency creates Factor VIII
deficiency owing to inability to protect FVIII from
proteolysis
-30 50% VWF sufficient for competent coagulation
-< 30% - soft tissue bleeding ; typical mucocutaneous
bleeding

TREATMENT
Mild bleeding resolve with local measures
- Limb elevation
- Ice packs
Moderate bleeding may respond to Estrogen, DDAVP
(triggers release of VWF from
storage organelles)
Severe Form commercial preparation with VWF and
Factor VIII