Pathology-bleeding disorders.ppt

Bleeding and coagulation
disorders
Dr Mrinalini Kotru
Prof Pathology, UCMS & GTBH

Components of haemostasis
Primary haemostasis Secondary Haemostasis
 Coagulation
factors
 Blood vessel wall
 Platelets

Disorders of hemostasis
 Disorders of primary hemostasis
 Vessel wall abnormalities
 Platelet disorders
 Qualitative
 Quantitive
 Disorders of secondary hemostasis
 Hereditary
 Hemophilia
 VWD
 Acquired

6 yr old boy presenting with multiple
ecchymotic patches and B/L knee swelling

Approach to diagnosis
 Detailed clinical history
 Type of bleeding
 Disorder of primary vs. secondary hemostasis
 Hereditary vs Acquired
 Laboratory evaluation of increased
bleeding tendency
 Screening coagulogram

Screening Coagulogram
11
 Platelet count
 PT
 APTT
 Additional
 Bleeding time
 TT
 S.Fibrinogen

Analysis
 Bleeding time
 Platelet count
 PT
 APTT
 TT
 S.Fibrinogen
Must for Screening for
increased bleeding
tendency

Platelet count
 Automated cell counters
 Different methods for analysis
 Impedance
 Optical – better
 Flourescence
 Flowcytometry
 Many times falsely low
 Confirm on peripheral smear

Prothrombin time
 Measures the time for plasma to clot in
presence of Tissue Factor and Calcium
 2,7,10 (Vit K dependent factors)
 Extrinsic & intrinsic pathway

 Normal -11-16 sec Thromboplasti
n

 Causes
 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 contact-
dependent 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
 Heparin (RVV normal)
 Hypo/paraproteinemia

 Shortened TT
 Faulty collection
 Marked elevation
 Heparin contamination
 Marked increased concentration of S.
Fibrinogen

What to do
with an
abnormal
result?
Further testing

How to collect specimens?
 Anticoagulant
 3.2 % Trisodium Citrate
 Vacutainer
 Tube made in the laboratory
 Sealed with para film

Diseases to be discussed
 Thrombocytopenia
 Hemophilia
 VWD
 DIC

Thrombocytopenia
 Normal count: 150-450 x 109/L
 Platelets remain in the circulation for 8-10
days
 Thrombocytopenia – when platelet count <150 x
109/L

The pathophysiology
of thrombocytopenia

Thrombocytopenia Associated with HIV
Infection
 Thrombocytopenia is common.
 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 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).

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 cutoff 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.

Acute ITP
 Isolated thrombocytopenia
 Resolves spontaneously most often in <6 months is termed
“Acute”
 The incidence peaks in the winter and spring, following the
incidence of viral infections.
 Approximately 7 to 28% of children with acute ITP develop
the chronic variety

Chronic ITP
 Lasting >6 months and requiring therapy to improve the
thrombocytopenia. (WINTROBE’S)
 According to INDIAN HEMOPHILIA AND THROMBOSIS
CENTRE:-
 If ITP has persisted >3 months
 If it has not responded to a splenectomy and the platelet count has been
<50,000 cells/mm3.
 In the pediatric setting, however, the designation for chronic ITP is
used only with duration of disease of ≥6 months.

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

Common presenting symptoms in patients with ITP
<1
%

Laboratory findings
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.

 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.
Diagnosis

Bone marrow
 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 microangiopathy refers to a combination of
1). Microangiopathic hemolytic anemia
2). Thrombocytopenia
3). Microvascular thrombosis, regardless of cause or specific
tissue involvement

3). Hemolytic uremic syndrome
a) Diarrhea positive (Infectious, Shiga toxin-associated)
Sporadic / Epidemic
b) Diarrhea negative:-Inherited complement regulatory protein
deficiencies (factor H, membrane cofactor protein, factor I)
4). Secondary thrombotic microangiopathy

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)

Regulation of von Willebrand factor (VWF)-dependent platelet
thrombosis by ADAMTS13

PATHOGENESIS OF TTP
Absence or decreased level of ADAMTS13

No timely cleavage of ULvWF multimers

Uncleaved ULvWF anchors to the endothelial cells via P-
selectin molecules

Passing platelets adhere via GPIb receptor

Induce adhesion and subsequent aggregation of platelets

Large, potentially occlusive platelet thrombi

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

 Coomb’s test is almost always negative.
 Normal
 plasma fibrinogen,
 prothrombin time and
 activated partial thromboplastin time
 ADAMTS13 related tests
 ADAMTS13 activity levels
 ADAMTS13 antigen levels
 Anti-ADAMTS13 autoantibodies

At the end of this lecture you
should know the following-

 To describe the normal coagulation pathway
 Differences between bleeding due to platelet
disorders and coagulation factor deficiency.
 Define Bleeding time (BT) and Clotting
 time (CT) and describe methods of estimation
 List the causes of prolonged BT and CT

Describe the principle of Prothombin time
(PT) and Activated partial thromboplastin
time (APTT) tests.
Enumerate the causes of increased PT and
PTT
List the causes of thrombocytopenia

 Etiopathogenesis, clinical features and lab
diagnosis of Immune thrombocytopenia (ITP).
 Differences between acute and chronic ITP.
 Differences between bleeding due to platelet
disorders and coagulation factor deficiency
 List the diseases causing non- immune
thrombocytopenia.

12) Etipathogenesis, clinical features and lab diagnosis
of Thrombotic thrombocytopenic purpura (TTP) and
Hemolytic uremic syndrome (HUS)
13) Short note on Von Willebrand disease (VWD)

Pathology-bleeding disorders.ppt

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