A brief approach to patients with bleeding disorders.

1. AN APPROACH TOAN APPROACH TO
PATIENT WITHPATIENT WITH
BLEEDINGBLEEDING
DISORDERDISORDER
Dr. Salma Afrose
Associate Professor
Department of Hematology

2. Haemostasis
Definition
Spontaneous arrest of bleeding when a small
vessel is cut or ruptured
Function
• To prevent blood loss from intact vessel
• Arrest of bleeding from injured vessel

3. Mechanism of Normal Haemostasis
Trauma
Vessel Constriction + Shed blood
Coagulation Platelet Adhesion &
release of ADP
Thrombin
Fibrin Platelet aggregation
(unstable plug)
Stable Haemostatic Plug

4. Haemostatic system is a complex mosaic of
activating inhibitory feedback or feed-forward
pathways, integrating it’s 5 major components
Vessel Wall Vessel Wall
 Platelets Platelet Inhibitors
 Coagulation Fibrinolysis
Blood flow
Production of local Prevention of
Haemostasis uncontrolled thrombosis

6. Damaged Endothelium
Role of Platelet in Haemostasis
vWF
1.Adhesion through vWF
2. Release of ADP, etc
3. Aggregation
4. Clot retraction
Platelet
Endothelial cell

7. FUNCTIONS OF
vWF:
1. vWF mediates
platelet adhesion at
site of injury
2. Stabilizes FVIII in
circulation

8. Pathways of Haemostasis
XII XIIa
XI XIa
IX IXa
VIIIa Ca2+
Phospholipid
VII
Ca2+
Tissue factor
VIIa
X Xa
VIIIa, Ca2+,
Phospholipid
Prothrombin (IIa)

9. Fibrinolytic Pathways
Plasminogen
Intrinsic Extrinsic
XIIa-pa u - pa
t - pa
PAI PAI
Plasmin
AP
Fibrin FDP

10. Protease action on Fibrinogen
& Fibrin
FIBRINOGEN PLASMIN Fibrinogen degradation
products X,Y,D,E
THROMBIN Fibrin monomer
Fibrinopeptide A & B
FIBRIN PLASMIN Fibrin degradation
[NON CROSS LINKED] products X,Y,D,E
FACTOR XIII
FIBRIN PLASMIN D dimer
[CROSS LINKED] X,Y,D,E

11. PRIMARY HYPER
FIBRINOGENOLYSIS
BLOOD
FREE PLASMIN FIBRINOGEN FDP
ENDOGENOUS ACTIVATOR
+
PLASMINOGEN
FIBRINOGENOLYSIS

13. Clinical Distinction Between Disorders
of Coagulation & Platelets or Vessel
Finding
Disorder of
Coagulation
Disorder of
Platelets or
Vessels
Petechiae Rare Characteristic
Deep dissecting
hematomas
Characteristic Rare
Superficial
ecchymoses
Common usually large
& solitary
Characteristic usually
small & multiple
Hemarthrosis Characteristic Rare
Delayed Bleeding Common Rare

14. Clinical Distinction Between Disorders of
Coagulation & Platelets or Vessel
Finding
Disorder of
Coagulation
Disorder of
Platelets or
vessel
Bleeding from
superficial cuts &
scratches
Minimal Persistent often
profuse
Sex of patient
80-90% of hereditary
forms occur only in
Male
Relatively more
common in females
Positive family history Common Rare

15. HAEMORRHAGIC
DISORDER

16. Definition:
These are a group of disorder of widely
differing aetiology which have in
common tendency to bleed due to defect
in the mechanism of haemostasis.

17. Clinical Features:
1.Spontaneous bleeding in to the skin,
mucous membranes & internal tissues.
2.Excessive or prolonged bleeding following
trauma or surgery.
3.Bleeding from more than one site.

18. Classification:
Due to Vascular Defects
• Acquired
– Simple easy bruising
– Senile purpura
– Symptomatic vascular
purpura
• Henoch-Scholein Purpura
• Scurvy
• Dysproteinaemia
– Miscellaneous
– Orthostatic purpura
– Mechanical purpura
• Congenital
– Hereditary haemorrhagic
telangiectasia
– Ehlar Danlos disease

19. Classification
Abnormal Platelet Production
• Acquired
– Idiopathic thrombocytopenic
purpura
– Drugs & chemicals
– Leukemias
– Aplastic anaemia
– Hypersplenism
– Disseminated lupus
erythematosus
– Dengue fever
Abnormal Platelet Production
• Neonatal & Congenital
– Auto-immune – mothers
with chronic ITP
– Drug administration to
mother

20. Classification
• Congenital
– Membrane receptor defects
– Glanzmann’s Thrombasthenia
– Enzyme defect
– Phospholipase deficiency
– Cycle-oxygenase deficiency
– Granuels defects
– Storage pool deficiency
• Acquired
– Leukemias
– Myelodysplasia
– Myeloproliferative
disorders
– Uraemia
– DIC
Due to Disorder of Platelet Function

21. Classification
• Hereditary
– X-linked recessive trait
• Haemophilia-A
• Haemophilia-B
– Autosomal recessive trait
• Afibrinogenemia
• Factor XIII deficiency
– Autosomal Dominant trait
• Von-Willbrand Disease
• Acquired
– Haemorrhagic disease
of new born
– Biliary obstruction
– Malabsorption of Vitamin K
– Drugs
– Liver disease
– DIC
Due to Disorder of Coagulation

22. THROMBOCYTOPENIA

23. Definition:
 Thrombocytopenia is defined as a reduction
in peripheral blood platelet count below the
normal lower limit of 150 x 109
/Liter .
 There is no absolute relation between
platelet count & occurrence & rate of
bleeding.

24. Bleeding is common –
<30000/L but not invariable
<10000/L bleeding is usual & often severe
Thrombocytopenia is accompanied by positive
tourniquet test & prolonged bleeding time.

25. Clinical Evaluation
• History Purpuric
Coagulation disorder
• Hereditary: Onset, positive family history
• Acquired: Drug, Viral infection
• Drug History
• Family History
• Clinical feature
• Physical examination

26. Lab Investigation
• Hemoglobin percentage
• ESR
• Total count & Differential count of WBC
• Platelet count
• Blood film – leukemia, platelet morphology
• Bleeding time (BT)
• Clotting time (CT)
• Prothrombin time (PT)
• Activated partial thromboplastin time (APTT)

27. Special Investigation
• Platelet function test
• Coagulation factor assay
• Fibrinogen Degradation Product (FDP)
• Fibrinogen assay
• VWF

28. Immune Thrombocytopenic
Purpura

29. Types of ITP
• Primary (Idiopathic)
• Secondary

30. Definition
The term idiopathic thrombocytopenic
purpura usually refers to thrombocytopenia in
which apparent exogenous etiologic factors
are lacking & in which diseases known to be
associated with secondary thrombocytopenia
have been excluded.

31. Classification
1. Acute Idiopathic Thrombocytopenic
Purpura
2. Chronic Idiopathic
Thrombocytopenic Purpura

32. Difference Between Acute & Chronic ITP
Feature Acute ITP Chronic ITP
Peak of Age Children of 2-
6 years
Adults 20-40
years
Sex
predilection
None 3:1 female to
male
Antecedent
infection
Common 1-3
weeks before
Unusual
Onset of
bleeding
Abrupt Insidious

33. Difference Between Acute & Chronic ITP
Feature Acute ITP Chronic ITP
Hemorrhagic
bullae in mouth
Present in
severe cases
Usually absent
Platelet count <20,000/ microL 30,000 – 80,000
/ microL
Eosinophilia &
lymphocytosis
Common Rare
Duration 2-6 weeks
rarely longer
> 6 months
Spontaneous
remissions
Occur in 80%
cases
uncommon

34. Patho-physiology
ITP is caused by platelet specific antibody that
bind to patient’s own platelet which are then
rapidly cleared from circulation by the
mononuclear phagocytic system via macrophage
Fc receptor.
The auto antibodies formed against platelet gp-
IIb/IIIa & gp-Ib/IX.
Splenic sequestration account for the shortest
survival of platelet in most patients but the liver
& RE cells of the bone marrow can play a major
role. The Spleen has also been implicated as site
of antibody production.

35. PATHOGENESIS
PLATELET
PLASMA CELL
ANTIBODY
COATED
PLATELET MACROPHAGE
REMOVAL OF ANTIBODY
COATED PLATELETS

38. Clinical Features
• Haemorrhagic manifestation of ITP are of
purpuric type
• Severity of bleeding depends on platelet
count
• Patient Usually present with cutaneous
purpura, petechiae, echymoses & easy
bruising (dry purpura)

39. On Examination
The outstanding feature is absence of
physical findings other than those due to
anemia:
• Anemia proportionate to the blood loss
• Purpuric rashes
• Splenomegaly in <10% cases

40. Lab Investigations:
• Hemoglobin percentage – Reduced
• CBC:
– WBC count normal / increased during
bleeding episodes
–Platelet count reduced
• Peripheral Blood film:
–Normocytic normochromic / microcytic
anemia
–Platelets are morphologically abnormal;
large, small & atypical forms

41. Lab Investigation
• Bleeding time: Raised
• Bone Marrow Examination: (in special
circumstances)
– Megakaryocyte & their precurosors are
present in normal / increased number &
shift to the left
– Other findings are normal
– Sometime there is erythroid hyperplasia
if anemia is severe enough

42. • Special Cases:
1. Not responding to treatment or relapse
2. Patients above 60 years
3. Before splenectomy

43. Diagnosis
• Bleeding manifestation without any
physical sign except signs of hemorrhage
• Isolated thrombocytopenia

44. Differential Diagnosis
• Aplastic anemia
• Acute leukemia
• Drug induced thrombocytopenia

45. Treatment
• Specific treatment
– Corticosteroid
– Immunosuppressive therapy
o
Azathioprine
o
Dexamethasone
o
Methylprednisolone
o
Ciclosporin
o
Dapsone
o
Vincristine
– Splenectomy

46. Treatment (Contd.)
• Supportive treatment
– Blood transfusion
– If emergency, platelet transfusion

47. Thrombotic Thrombocytopenic Purpura
It is a rare disease which is characterized by –
–Fever
–Thrombocytopenic purpura
–Hemolytic anemia
–Fluctuating neurological disturbances of
variable nature
–Renal failure
It occurs in all age & have the Lab finding like
HUS

48. Hemolytic Uremic Syndrome

49. Definition
Hemolytic uremic syndrome is a triad of
microangiopathic hemolytic anameia,
thrombocytopenia & acute renal insufficiency.

50. Aetiology
 E.coli 0156:H7
 Shigella dysentery serotype-I
(less frequently)
Types

51. Pathogenesis
Toxin Absorption from Gut in to blood
Attachment to the receptor membrane
Endocytosed Cytolysis Endothelial
swelling &
desquamation
Platelet & Coagulation
activation

52. Symptoms
• Bloody diarrhoea
• Severe abdominal pain
• Vomiting
• Passage of dark red urine which may lead
to Oliguria or anuria

53. Signs
• Anemia
• Jaundice
• Bleeding manifestation

54. Lab Findings
• Hemoglobin – Decreased
• Platelet count – Decreased
• Peripheral Blood film - Evidence of hemolysis
present
• Serum bilirubin – Increased
• Blood urea – Increased
• Hemoglobinaemia - Present
• Hemoglobinurea – Present
• Stool Culture

55. Treatment
• Fluid & electrolyte balance
• Dialysis if required
• Medication, such as anti-biotic if
indicated
• Blood / blood product transfusion if
necessary

56. Clinical Features
• Patient may present with mucosal
bleeding
–Epistaxis
–Haematuria
–Menorrhagia
–Melaena
• Intracranial Haemorrhage (rare)

57. Hemophilia

58. Definition
It is an inherited & X-linked recessive disease
Classification
Haemophilia A – Factor VIII
deficiency
Haemophilia B – Factor IX deficiency

59. The daughters of affected males are obligate carriers but the sons are
normal.

60. Clinical Features
Bleeding tendency usually appear in
infancy
In mild cases it may not become
apparent until adolescent or adult life
Coagulation factor <1% is severe
Coagulation factor 1-5% is moderate
Coagulation factor 6-40% is mild

61. Clinical Feature (contd.)
Hemarthrosis
Bleeding from skin
Tissue bleeding
Epistaxis
Bleeding from central nervous system
Urogenic & gastro-intestinal bleeding

62. Signs
Anemia
Chronic arthritic changes in joints
Haematoma

63. Diagnosis
History
Age
Sex
History of maternal side
Physical findings
Clinical findings

64. Investigation
Bleeding time – Normal
Platelet count – Normal
Clotting time – Raised
Prothrombin time – Normal
APTT – Raised
Factor VIII / IX assay - Deficient

65. Management
General Supportive treatment
Rest
Local haemostatic measure
Replacement therapy
FFP
Factor VIII or IX concentrate
Blood transfusion
Fibrinolytic inhibitors
Aminocapric acid
Tranexamic acid

66. Disseminated Intravascular
Coagulation

67. Definition
DIC is an acquired syndrome occurs as a
result of inappropriate & excessive
activation of haemostatic system that
leads to the formation of micro-thrombi
throughout the circulation of the body
& consumption of platelet, fibrin &
coagulation factors

68. Investigations
CBC –
Bleeding Time - Raised
Platelet Count – Decreased
Prothrombin Time – Raised
APTT – Raised
Fibrinogen Level – Reduced
Fibrin Degradation Product – Raised
Blood film -

69. PERIPHERAL BLOOD SMEAR IN DIC
MICROSPHEROCYTE
SCHISTOCYTE

70. Treatment
Treatment of the cause
Replacement of coagulation factors &
platelet
Anti-coagulant therapy