2. Vessel Defects Causing Bleeding
Begins with bleeding episode in presence of normal l
ab tests for coagulation function
Types divided into hereditary and acquired
Symptoms are usually of the superficial ones.
Usually these diseases are diagnosed by exclusion. Af
ter ruling out PLT disorders, coagulation or fibrinolyt
ic disorders in a patient who has bleeding symptoms.
3. Vascular Diseases
PLT count and screening tests for coagulation
factors are usually normal.
PLT function tests such as bleeding time and o
ther PLT function tests are also normal, but BT
may be prolonged in some vascular diseases.
4. They are very rare, and while bleeding is a com
mon symptom, hemostasis tests are NOT neces
sary for diagnosis.
Inherited vascular disorders
5. Hereditary Connective Tissue Defects
Defect affects ability to support vessel walls
Examples
– Ehlers-Danlos Syndrome
Lack of structural tissue support (collagen disorders)
Skin elasticity and fragility.
Hypermobility of joints
Evidenced by bleeding/bruising
Recurrent joint problems & scarring of the face.
The most serious is deficient of type III collagen (blood vesse
l type). Which leads to Acute & sever Internal bleeding & sud
den death.
6. Hereditary Vessel Disease
Hereditary Haemorrhagic telangiectasia (HHT)
Inherited as autosomal dominant trait
Involves bleeding from abnormally dilated vessels “telangiectasia
s”
Vessels involved do not contract normally and collapse easily
Patient has pinpoint lesions (tiny areas of bleeding)
Lesions occur on face, hands and feet
May develop at all ages
Blood loss may cause anemia
Diagnosis based on physical appearance
8. Acquired Connective Tissue Defects
Vitamin C Deficiency (Scurvy)
Caused deficient Vitamin C
Vitamin C required for vessel collagen integrity
Acts as “cement” holding endothelial cells together
Lack of Vitamin C prevents proper collagen formation
Result: bleed and vessel fragility
Symptoms include gum bleeding, petechiae and bleedi
ng into tissues and muscles
Treated with Vitamin C
9. Acquired Connective Tissue Defects
Senile Purpura
Occurs in elderly population
Usually benign
Collagen degradation/loss affects vessel int
egrity
Bruising on arms/hands
No treatment/therapy available
13. Thrombocytopenia
Reduced platelet count.
The most common cause of excess or abnormal
bleeding.
As anemia is a symptom of a disease as we hav
e seen in Hematology #1, thrombocytopenia is a
lso a symptom of a disease!
14. Do not forget to assure that the case
you have is a real thrombocytopenia
and not Pseudothrombocytopenia
Platelet clumping, or a
ggregation
Platelet Satelltis
m
Pseudothrombocytopenia
15. Platelet count Symptoms
50-100 X109/L Prolonged bleeding following trauma
< 50X109/L Easy bruising
Purpura following minor trauma
< 20 X109/L Spontaneous bleeding
Petechiae
May suffer spontaneous internal and intracranial bl
eeding
Thrombocytopenia
18. General characteristics of platelet disor
ders
characterized by variable mucocutaneous bleedin
g manifestations.
excessive hemorrhage may follow surgical proced
ures or trauma.
Platelet counts and morphology are normal.
prolonged bleeding time,
Abnormal Platelet aggregation and secretion studi
es
19. Thrombocytopenia
Usually mucosal bleeding
Epistaxis, menorrhagia, and GI bleeding is c
ommon
Trauma does not usually cause bleeding
20. Thrombocytopenia
Three mechanisms of Thrombocytopenia
– Decreased production
Usually chemotherapy, myelophthisic disease, or BM eff
ects of alcohol or thiazides
– Splenic Sequesteration
Rare
Results from malignancy, portal hypertension, or increas
ed Splenic RBC destruction ( hereditary spherocytosis, a
utoimmune hemolytic anemia)
– Increased Destruction
21. Thrombocytopenia
Immune thrombocytopenia
– Multiple causes including drugs, lymphoma, leukemia, colla
gen vascular disease
– Drugs Include
Digitoxin, sulfonamindes, phenytoin, heparin, ASA, cocai
ne, Quinine, quinidine, glycoprotein IIb-IIa antagonists
– After stopping drugs platelet counts usually improve over 3 t
o 7 days
– Prednisone (1mg/kg) with rapid taper can shorten course
22. ITP
Diagnosis of exclusion
Associated with IgG anti-platelet antibody
Platelet count falls to less that 20,000
23. ITP
Acute Form
– Most common in children 2 to 6 years
– Self Limited and > 90% remission rate
– Supportive Treatment
– Steroids are not helpful
24. ITP
Chronic Form
– Adult disease primarily
– Women more often than men
– Symptoms include: easy bruising, prolonged men
ses, mucosal bleeding
– Bleeding complications are unpredictable
– Mortality is 1%
– Spontaneous remission is rare
25. ITP
Chronic Form
– Hospitalization common because of a complex dif
ferential diagnosis
– Platelet transfusions are used only for life threate
ning bleeding
26. TTPHUS
Exist on a continuum and are likely the same diseas
e
Diagnosed by a common pentad
– Microangiopathic Hemolytic Anemia: Schistocytes membran
es are sheared passing through microthrombi
– Thrombocytopenia: More sever in TTP
– Fever
– Renal Abnormalities: More prominent in HUS: include Renal
insufficiency, proteinuria, hematuria, and renal failure
– Neurologic Abnormalities: hallmark of TTP 1/3 of HUS:, con
fusion,coma
27. TTPHUS
Labs
– PT, PTT, and fibrinogen are within reference rang
e
– Helmet Cells (Shistocytes) are common
28. TTPHUS
HUS
– Most common in infants and children 6mo - 4 year
s
– Strongest association to E. coli but also associate
d with virus
29. TTPHUS
HUS
– Treatment
Mostly supportive
Plasma exchange reserved for sever cases
Avoid antibiotics with Ecoli
– May actually increase verotoxin production.
– May be helpful with cases of Shigella dysenteriae
30. TTPHUS
AVOID PLATELET TRANSFUSION
– May lead to additional microthrombi in circulation
– Transfuse only with life threatening bleeding
31. Significant Lab Data in Defects of
Primary Hemostasis
Test Vascular Disorder Thrombocytopenia PLT Dysfunction
PLT Count N D N
PT N N N
APTT N N N
BT N or ABN ABN N or ABN
36. Bernard-Soulier Syndrome
First described in 1948 by Jean Bernard and Jean-Pi
erre Soulier; French hematologists
Bernard J, Soulier JP: Sur une nouvelle variete de dystrophie t
hrombocytaire hemarroagipare congenitale. Sem Hop Paris 24
:3217, 1948
AR; characterized by moderate to severe thrombocyt
openia, giant platelets, and perfuse/spontaneous ble
eding
Basis for the disease is deficiency or dysfunction of t
he GP Ib-V-IX complex
37. Bernard-Soulier Syndrome
Decreased GP Ib-V-IX leads to decreased platelet adhesi
on to the subendothelium via decreased binding of vWF
Approximately 20,000 copies of GP Ib-V-IX per platelet
GP 1b: heterodimer with an alpha and beta subunit
The gene for GP Ib alpha is located on chromosome 17;
GP Ib beta: chromosome 22; GPIX and V: chromosome 3
Most mutations are missense or frameshifts resulting in p
remature stop codons
Most mutations involve GP Ib expression (rare GP IX mut
ations have been described; no mutations in GP V)
38. Diagnosis
Prolonged bleeding time, thrombocytopenia (
plt<20 K), peripheral smear shows large plat
elets (mean diameter >3.5 microns)
39.
40. Diagnosis
Platelet aggregation studies show normal ag
gregation in response to all agonists except
Ristocetin (opposite pattern than thrombasth
enia)
Flow cytometry: decreased expression of mA
bs to CD 42b (GPIb), CD42a(GPIX), CD42d(
GPV)
41.
42. Glanzmann’s Thrombasthenia
Eduard Glanzmann (1887-1959), Swiss pediatri
cian
Reported a case of a bleeding disorder starting
immediately after birth
W. E. Glanzmann:Hereditäre hämorrhägische
Thrombasthenie. Ein Beitrag zur Pathologie
der Blutplättchen.
Jahrbuch für Kinderheilkunde, 1918; 88: 1-42
, 113-141.
43.
44. Glanzmann’s
IIbIIIa most abundant platelet surface recepto
r (80,000 per platelet)
IIbIIIa complex is a Ca++ dependent heterodi
mer
Genes for both subunits are found on Chrom
osome 17
Disease is caused by mutations (substitution,
insertion, deletion, splicing abnormalities) in
genes encoding for IIb or IIIa resulting in qual
itative or quantitative abnormalities of the pro
teins
45. Glanzmann’s
Fundamental defect of thrombasthenic patien
ts is the inability of the platelets to aggregate
Other problems: platelets do not spread nor
mally on the subendothelial matrix (due to lac
k of IIbIIIa – vWF/fibronectin interaction)
46. Glanzmann’s
Patients present with wide spectrum of disea
se
Like thrombocytopenic bleeding: skin, mucou
s membrane (petichiae, echymoses), recurre
nt epistaxis, GI hemorrhage, menorrhagia, a
nd immediate bleeding after trauma/surgery
47. Diagnosis
Platelet count and morphology are normal
Bleeding time prolonged
The hallmark of the disease is severely re
duced or absent platelet aggregation in re
sponse to multiple agonists ie ADP, throm
bin, or collagen (except Ristocetin)
Flow cytometry: decreased mAb expressi
on of CD41 (GPIIb) and CD61 (GPIIIa)
48.
49. Storage Pool Defects
Classified by type of granular deficiency or s
ecretion defect.
Dense body deficiency, alpha granule deficie
ncy (gray platelet syndrome), mixed deficienc
y, Factor V Quebec
50. Defects in secondary aggregation
Deficiency of contents of one of granules
Inheritance is variable (heterogeneous group)
Bleeding is usually mild to moderate but can
be exacerbated by aspirin
Clinical: easy bruising, menorrhagia, and exc
essive postpartum or postoperative bleeding
51. Dense body deficiency
decreased dense bodies (
ADP, ATP, calcium, pyrop
hosphate, 5HT)
Normal platelet contains
3-6, 300 micron dense bo
dies
52. Chediak-Higashi
described by Beguez Cesar in 1943, Steinbrinck in 1
948, Chédiak in 1952, and Higashi in 1954
AR; abnormal microtubule formation and giant lysoz
omal granules are present in phagocytes and melan
ocytes
No degranulation/chemotaxis = recurrent bacterial inf
ections
Dense-body granules decreased/absent
54. LAB Screening Tests
Lab screening tests are based on the length
of time that it takes a clot to form in plasma.
So screening tests does not differentiate bet
ween qualitative or quantitative defects!
55. Types of Bleeding Disorders
Hemophilia A (factor VIII deficiency)
Hemophilia B (factor IX deficiency)
von Willebrand Disease (vWD)
Other
57. What is Hemophilia?
Hemophilia is an inherited blee
ding disorder in which there is a
deficiency or lack of factor VIII (
hemophilia A) or factor IX (hem
ophilia B)
58. Hemophilia A and B
Hemophilia A Hemophilia B
Coagulation factor deficiency Factor VIII Factor IX
Inheritance X-linked X-linked
recessive recessive
Incidence 1/10,000 males 1/50,000 males
Severity Related to factor level
<1% - Severe - spontaneous bleeding
1-5% - Moderate - bleeding with mild injury
5-25% - Mild - bleeding with surgery or trauma
Complications Soft tissue bleeding
59. Inheritance of Hemophilia
Hemophilia A and B are X-linked recessive di
sorders
Hemophilia is typically expressed in males a
nd carried by females
Severity level is consistent between family m
embers
60. Genetics of Hemophilia A
The gene F8 is located in the X chromosome, at Xq2
8, near telomeric region.
It consists of 26 exons, and 25 introns.
The F8 gene spans 186 Kb.
Mature RNA is 8.8 Kb.
The F8 protein is 2351 amino acid.
The leader sequence is 19 a.a.
61. Detection of Hemophilia
Family history
Symptoms
– Bruising
– Bleeding with circumcision
– Muscle, joint, or soft tissue bleeding
Hemostatic challenges
– Surgery
– Dental work
– Trauma, accidents
Laboratory testing
62. Screening Tests
in Secondary Hemostasis Defects
PT is prolonged or (test extrinsic pathway)
APTT is prolonged or (test intrinsic pathway)
Both are prolonged.
Platelets are normal in count and function.
TT (thrombin time): prolonged in disorders of fibrinog
en.
If any test is abnormal of these screening tests, addit
ional testing may resolve the disorder>>>>
63. Additional Testing
Specific Factor Assays.
Fibrinogen Level
D-Dimer
FDP’s
Antithrombin Level
The list continues to expand………….
64. Degrees of Severity of Hemophilia
Normal factor VIII or IX level = 50-150%
Mild hemophilia
– factor VIII or IX level = 6-50%
Moderate hemophilia
– factor VIII or IX level = 1-5%
Severe hemophilia
– factor VIII or IX level = <1%
65. Hemophilia Prevalence
Hemophilia A; 1 in 5000 population
– coagulation factor VIII deficiency
Hemophilia B; 1 in 30000 population
– coagulation factor IX deficiency
Hemophilia A is six-fold more prevalent than
hemophilia B.
66. Types of Bleeds
Joint bleeding - hemarthrosis
Muscle hemorrhage
Soft tissue
Life threatening-bleeding
Other
71. Factor VIII Concentrate
Intravenous infusion
– IV push
– Continuous infusion
Dose varies depending on type of bleeding
– Ranges from 20-50+ units/kg. body weight
Half-life 8-12 hours
Each unit infused raises serum factor VIII lev
el by 2 %
72. Factor IX Concentrate
Intravenous infusion
– IV push
– Continuous infusion
Dose varies depending on type of bleeding
– Ranges from 20-100+ units/kg. body weight
Half-life 12-24 hours
Each unit infused raises serum factor IX level
by 1%
74. vWD
Family of bleeding disorders
Caused by a deficiency or an abnormality of von Will
ebrand Factor
75. vWF
VWF gene : short arm of chromosome 12
VWF gene is expressed in endothelial cells and megakaryocytes
76. vWF Function
Adhesion
Mediates the adhesion of
platelets to sites of vascul
ar injury (subendothelium)
Links exposed collage
n to platelets
Mediates platelet to platel
et interaction
Binds GPIb and GPIIb
-IIIa on activated plate
lets
Stabilizes the hemost
atic plug against shea
r forces
77. vW Factor Functions in Hemostasis
Carrier protein for Factor VIII (FVIII)
– Protects FVIII from proteolytic degradation
– Localizes FVIII to the site of vascular injury
– Hemophilia A: absence of FVIII
78. Frequency
Most frequent inherited bleeding disorder
– Estimated that 1% of the population has vWD
– Very wide range of clinical manifestations
– Clinically significant vWD : 125 persons per million populatio
n
– Severe disease is found in approximately 0.5-5 persons per
million population
Autosomal inheritance pattern
– Males and females are affected equally
79. vWD Classification
Disease is due to either a quantitative deficiency of vWF or to fu
nctional deficiencies of vWF
– Due to vWF role as carrier protein for FVIII, inadequate amo
unt of vWF or improperly functioning vWF can lead to a resu
ltant decrease in the available amount of FVIII
80. vWD Classification
3 major subclasses
– Type I: Partial quantitative deficiency of vWF
Mild-moderate disease
70%
– Type II: Qualitative deficiency of vWF
Mild to moderate disease
25%
– Type III: Total or near total deficiency of vWF
Severe disease
5%
Additional subclass
– Acquired vWD
81. Clinical Manifestations
Most with the disease have f
ew or no symptoms
For most with symptoms, it i
s a mild manageable bleedin
g disorder with clinically sev
ere hemorrhage only with tra
uma or surgery
Types II and III: Bleeding epi
sodes may be severe and p
otentially life threatening
84. vWD: aPTT and PT
aPTT
– Mildly prolonged in approximately 50% of patients with vWD
Normal PTT does not rule out vWD
– Prolongation is secondary to low levels of FVIII
PT
– Usually within reference ranges
86. DIC
An acquired syndrome chara
cterized by systemic intrava
scular coagulation
Coagulation is always the ini
tial event.
Most morbidity and mortalit
y depends on extent of intra
vascular thrombosis
Multiple causes
6
Thrombosis
Thrombosis
Fibrin
Fibrin
Red Blood Cell
Red Blood Cell
Platelet
Platelet
WWW. Coumadin.com
87. DIC
An acquired syndrome ch
aracterized by systemic in
travascular coagulation
Coagulation is always the
initial event
88. Pathophysiology of DIC
Activation of Blood Coagulation
Suppression of Physiologic Anticoagulant Pat
hways
Impaired Fibrinolysis
89. Pathophysiology of DIC
Activation of Blood Coagulation
– Tissue factor/factor VIIa mediated thrombin gener
ation via the extrinsic pathway
complex activates factor IX and X
– TF
endothelial cells
monocytes
Extravascular:
– lung
– kidney
– epithelial cells
90. Pathophysiology of DIC
Suppression of Physiologic Anticoagulant Pat
hways
– reduced antithrombin III levels
– reduced activity of the protein C-protein S system
– Insufficient regulation of tissue factor activity by tis
sue factor pathway inhibitor (TFPI)
inhibits TF/FVIIa/Fxa complex activity
91. Pathophysiology of DIC
Impaired Fibrinolysis
– relatively suppressed at time of maximal activation
of coagulation due to increased plasminogen activ
ator inhibitor type 1
92. Diagnosis of DIC
Presence of disease associated with DIC
Appropriate clinical setting
– Clinical evidence of thrombosis, hemorrhage or b
oth.
Laboratory studies
– no single test is accurate
– serial test are more helpful than single test
93. Conditions Associated With DIC
Malignancy
Leukemia
Metastatic disease
Cardiovascular
Post cardiac arrest
Acute MI
Prosthetic devices
Hypothermia/Hyperthermia
Pulmonary
ARDS/RDS
Pulmonary embolism
Severe acidosis
Collagen vascular dise
ase
98. Laboratory Tests Used in DIC
D-dimer*
Fibrin Degradation Prod
Platelet count
Thrombin time
Fibrinogen
Prothrombin time
Activated PTT
Reptilase time
Coagulation factor levels
99. Laboratory diagnosis
Thrombocytopenia
– plat count <100,000 or rapidly declining
Prolonged clotting times (PT, APTT)
Presence of Fibrin degradation products or positive D
-dimer
Low levels of coagulation inhibitors
– AT III, protein C
Low levels of coagulation factors
– Factors V,VIII,X,XIII
Fibrinogen levels not useful diagnostically
100. Differential Diagnosis
Severe liver failure
Vitamin K deficiency
Liver disease
Thrombotic thrombocytopenic purpura
Congenital abnormalities of fibrinogen
