Hematology 2 Lecture Notes Platelet Quantitative Disorders

Hematology 2 Lecture Notes
Quantitative Platelet Disorders

- Characterized by the increase or decrease in
platelet count.
Classified into:
A. Thrombocytopenia refers to platelet count of
less than 150,000/cumm
B. Thrombocytosis refers to platelet count of
more than 450, 000/cumm
A. Thrombocytopenia
Results from:
1. Deficient Platelet Production
2. Abnormal Distribution
3. Increased Destruction
4. Sample Integrity and Preanalytic Variables
1. Deficient Platelet Production
Due to:
1.1 Megakaryocytic Hypoplasia
1.2 Ineffective Thrombopoiesis
1.3 Bone Marrow Replacement
1.1 Megakaryocytic Hypoplasia
Classified into:
1.1.1. Inherited Megakaryocytic Hypoplasia
1.1.2. Acquired Megakaryocytic Hypoplasia
1.1.1. Inherited Megakaryocytic Hypoplasia
- These conditions are rare but must always be
considered when the platelet count is low,
especially when there is no platelet antibodies can
be demonstrated.
Disease associated:
1.1.1.1. Fanconis Anemia (FA)
1.1.1.2. Thrombocytopenia with Absent Radius
(TAR)
1.1.1.3. Amegakaryocytic Thrombocytopenia (AMT)
1.1.1.1. Fanconis Anemia (FA)
- Inherited syndromes with autosomal-recessive
transmission.
- Characterized by marked hypomegakaryocytic
thrombocytopenia, skeletal deformities, and sexual
and mental retardation.
- Most notable skeletal deformity is the absence or
hypoplastic thumbs and short stature.
- Thrombocytopenia, anemia, and leukopenia.
- The onset of thrombocytopenia is from 18
months to 10 years.
- Hematopoietic defect exists in the stem cell level
which involves all of the hematopoietic cell lines.
1.1.1.2. Thrombocytopenia with Absent Radius

(TAR)
- Inherited syndromes with autosomal-recessive
transmission.
- Most notable skeletal defect is the bilateral
deformity, absence of the forearm bones.
- Neonates present severe thrombocytopenia at
birth, and normal leukocyte and erythrocyte count.
- Hematopoietic defect lies on the megakaryocytic
progenitor cells.
- 90% of neonates with TAR die in the first year of
life.
- If patients survive for the first 4 months of life,
there is a good chance of the normalization of the
platelet count by 5 6 years.
- Mental Retardation happens in 7% of the patients
due to intracranial hemorrhage.
- Diagnosed using ultrasound and absence of radii
can be detected as early as 18 weeks.
- Thrombocytopenia can be confirmed using
platelet count on a fetal blood sample.
- If indicated, platelets can be transfused into the
umbilical vein to reduce the risk of in utero
hemorrhage, as well as immediately after delivery.
- The cause of thrombocytopenia is not yet known
but it has been suggested that it could be due to a
maturational defect or arrest in the committed
stem cells.
- An immune mediated defect has also been
proposed, but failure of immunoglobulin and
steroid administration to correct the
thrombocytopenia suggests otherwise.
1.1.1.3. Amegakaryocytic Thrombocytopenia (AMT)
- - Inherited syndromes with autosomal-recessive
transmission.
- Thrombocytopenia persists and the patient
deteriorates.
- In some cases there is complete failure of the
bone marrow which affects all hematopoietic cell
lines.
1.1.2 Acquired Megakaryocytic Hypoplasia
Disease associated:
1.1.2.1. Aplastic Anemia
1.1.2.2. Myelophthisic Thrombocytopenia
1.1.2.3. Prolonged Hypoxia
Primary Hemostatic Disorders Platelet Quantitative Disorders

1.1.2.1 Aplastic Anemia
- Generalized bone marrow suppression leading to
a decrease in all cell types.
- Peripheral blood pancytopenia.
- Bone marrow is severely hypoplastic (decreased
in number of precursor cells of all the cell lines), or
aplastic (absence of all bone marrow cells).
- Normal hematopoietic cells are replaced by fat.
- The name of the disorder is misleading due to the
word anemia which would mean the decrease in
the erythrocytes, however the most serious clinical
problems relate to neutropenia, and
thrombocytopenia.
- It is better called myeloaplasia, meaning
decreased development of all bone marrow cells.
- There are milder forms of the disorder such as the
drug toxicity induced bone marrow hypoplasia.
- Important note in Aplastic Anemia that there are
no immature myeloid cells in the peripheral blood.
- Diagnostic criteria for Severe Aplastic Anemia:
1. Bone Marrow Cellularity - <25% of normal
- <50% of normal
cellularity with
<30% hematopoietic
cells
2. Plus any two of the following:
Peripheral blood
Granulocytes - <0.5X109/L
Platelets
- <20X109/L
Anemia with - <1% reticulocytes (corrected for
hematocrit)
- This findings along with aplastic or hypoplastic
marrow where hematopoietic cells are replaced
with fat cells, helps to differentiate Aplastic Anemia
from a number of other pancytopenic conditions.
- The incidence is low before the age of 1 year,
then increases at an intermediate rate until the age
of 50.
- Acquired Aplastic Anemia may be the
consequence of toxic chemical or physical agents.
Drugs associated with Aplastic Anemia:
A. Antimicrobials Chloramphenicol, Sulfonamides
B. Anti-inflammatory/Antirheumatic Agents
Phenylbutazone, Oxyphenbutazone, Gold salts,
Indomethacin.
C. Anticonvulsants Phenytoin, Methoin
D. Diuretics Chlorothiazide
E. Antithyroid Propylthiouracil, Methylthiouracil,
Carbimazole, Potassium perchlorate, Thoicyanate
F. Oral Hypoglycemic Agents Chlorpropamide
G. Antimalarials Amodiaquine, Chloroquine,
Mepacrine (qionacrine)
- Chloramphenicol is the classic drug associated
with marrow aplasia, characterized by the
appearance vacuolated cells in the bone marrow,
especially the erythroid series.
- Radiation may damage stem cells or the

hematopoietic microenvironment.
- Exposure to long term, low-dose irradiation have
an increased incidence of having aplastic anemia.
- Exposure to acute, high-dose radiotherapy,
radioactive isotope administration, or working in
unsafe nuclear power plants can result in rapidly
developing bone marrow aplasia and death.
- Mechanisms by which drugs and related
compounds induce thrombocytopenia appears to
be drug toxicity rather than immunologic response.
1.1.2.2 Myelophthisic Thrombocytopenia
- refers to the crowding out of megakaryocytic
precursors by space-occupying lesions in the bone
marrow.
- Invasion of the marrow by nonmegakaryocytic
tissues occur in many conditions such as:
1. Myelofibrosis Connective tissue accumulation
in the bone marrow.
2. Metastatic Tumor Spread of cancer cells in the
bone marrow
3. Leukemia Abnormal increase of the leukocyte
precursor in the bone marrow
4. Hodgkin and nonhodgkins lymphoma
Abnormal proliferation of B lymphocytes in the
bone marrow
5. Microangiopathic hemolytic anemia Diseases
such as the HUS, TTP, DIC, and malignant
hypertension.
6. Osteopetrosis abnormal absence of bone
cavity thus giving no space for bone marrow cells
to occupy.
1.1.2.3 Prolonged Hypoxia
- Great expansion of the erythroid precursor cells
thus causing the committed megakaryocytic
progenitor pool to reduce in number.
- Megakaryocytopoiesis is abnormal due to an
acquired stem cell defect induced by the prolonged
hypoxia.
1.2 Ineffective Thrombopoiesis
- characterized by a normal to increased number of
megakaryocytes in the bone marrow, normal
platelet life span, and decreased platelet count.
Can be classified into:
1.2.1. Inherited Ineffective Thrombopoiesis
1.2.2. Acquired Ineffective Thrombopoiesis
1.2.1. Inherited Ineffective Thrombopoiesis
Disease associated:
1.2.1.1. May-Hegglin Anomaly
1.2.1.2. Bernard-Soulier Syndrome
1.2.1.3. Wiskott-Aldrich Syndrome
1.2.1.4. Paris-Trousseau Syndrome

1.2.1.1. May-Hegglin Anomaly
- A rare autosomal-dominant anomaly that is
characterized by Dhle Bodies within leukocytes.
- Variable degree of thrombocytopenia, and giant
platelets.
- The degree of thrombocytopenia ranges from 20
120X109/L with an MPV of 15 20 fL.
- Platelet function is normal
- Increased platelet associated antibodies (IgG) are
observed.
- The large platelets may be hypogranular
- Bleeding time may be prolonged and abnormal
clot retraction.
- The degree of abnormality seems to be
proportional to the extent of thrombocytopenia,
which may be more accurately reflected by total
platelet mass than platelet number.
- Abnormal microtubule organization may play a
role in the defective platelet formation in this
disorder.
- Platelet aggregation studies are normal.
1.2.1.2. Bernard-Soulier Syndrome
- Inherited disorder associated with platelet
Ineffective Thrombopoiesis due to the absence of
the GPIb subunit and Filamin A.
- Absence of such glycoprotein subunit causes the
defect in the adhesion in platelets.
1.2.1.3. Wiskott-Aldrich Syndrome
- An Immunodeficiency Syndrome characterized by
severe thrombocytopenia and excessively small
platelets that leads to bleeding.
- Inherited disorder associated with ineffective
thrombopoiesis.
- The small platelets are rapidly removed by the
spleen because these platelets are nonfunctional,
thus causing now the thrombocytopenia.
1.2.1.4. Paris-Trousseau Syndrome
- A congenital thrombocytopenia with a mild
hemorrhagic tendency that occurred in a woman
and her child.
- Thrombocytopenia is due to ineffective
Thrombopoiesis was indicated by the increased
number of bone marrow megakaryocytes.
- A large percentage of these bone marrow
megakaryocytes are micromegakaryoctes, small in
size thus decrease platelet yield during
thrombopoiesis or platelet shedding.
- Platelets are of normal lifespan.
- Giant platelet -granules have been detected due
to the fusion of -granules.
- The condition is attributed to a deletion of the
distal part of one chromosome 11 at 11q23.
1.2.2 Acquired Ineffective Thrombopoiesis

Agents associated:
1.2.2.1. Alcohol Intake
1.2.2.2. Vitamin B12 Deficiency
1.2.2.3. Paroxysmal Nocturnal Hemoglobinuria
1.2.2.1. Alcohol Intake
- Ethanol suppresses thrombopoiesis at the level of
maturing megakaryocytes and decreases platelet
life span.
- Rare clinically significant hemorrhage has been
observed.
- Platelet count starts to normalize after 2 5 days
after abstinence.
1.2.2.2. Vitamin B12 Deficiency
- Vitamin B12 is necessary for DNA synthesis.
- Causes megaloblastic changes to RBCs.
Possible causes of the deficiency:
1. Dietary Deficiency caused by high vegetarian
diet, avoidance of meat, eggs, and milk.
2. Vitamin B12 Malabsorption caused by the
difficulty in extraction of the food bound vitamin
B12.
3. Gastrectomy (excision of the stomach) due to
removal of the parietal cells thus causing deficiency
of Castles intrinsic factor and thus failure to absorb
vitamin B12.
4. Intrinsic Factor Molecular Defect incapability of
the Intrinsic Factor in ileal B12 absorption.
5. Small Bowel Bacterial Overgrowth Low
concentration of bowel flora due to the following
factors:
A. Normal peristalsis, which prevents stasis and
encourages recirculation of intestinal contents.
B. Gastric acid secretion.
Conditions that can promote bacterial growth
include small bowel diverticulosis, blind loops and
pouches, and achlorhydria.
- Excessive bacterial growth successfully competes
for ingested B12, making it unavailable for ileal
absorption.
- In Schillings Test the absorption is not corrected
by administration of the Intrinsic Factor.
- Treatment with antibiotics usually corrects the
problem.
6. Fish Tapeworm Disease Diphyllobothrium
latum, a common parasite of freshwater fish.
The D. latum interferes with B12 absorption by
competing with Intrinsic Factor for binding B12,
over time, this results in B12 deficiency.
7. Ileal Disease B12 is absorbed in the ileum, ileal
resection, bypass, or disease often leads to B12
malabsorption. Crohns disease, also known as
regional enteritis, is one of the better-known
disease that affects the ileum. Patients with

Crohns disease sometimes develop megaloblastic
anemia. Vitamin B12 and folate deficiency may
occur together in Crohns disease.
8. Human Immunodeficiency Virus and Other
Causes Vitamin B12 levels are decreased due to
malabsorption. Helps to predict those patient
whose disease will progress most rapidly. The
earliest laboratory indicator of tissue B12 deficiency
in AIDS patients was a low serum transcobalamin II
B12 binding protein (which is responsible for B12
transport). This parameter was found to be
decreased despite the normal serum B12 and total
homocysteine and a normal classic Shcilling test.
However the food Schilling test is abnormal in
these patients.
- Certain drugs, hemodialysis, and normal nearterm preganancy can also cause B12 deficiency.
1.2.2.3. Paroxysmal Nocturnal Hemoglobinuria
- Occurs more often in the third to fifth decades of
life, although it has been reported in childhood and
old age.
- Caused by a defect of insidious (gradual and
subtle) onset, which arises from mutation in a
single bone marrow precursor that results in an
abnormal clone of bone marrow stem cells
affecting erythrocytes, leukocytes, and platelets.
- Defect involves the inability to produce the first
enzyme necessary for the synthesis of the
glycosylphosphatidylinositol anchor (GPI anchor).
The GPI anchor is required for the linkage or
anchoring of some proteins (like decay accelerating
factor [DAF], Glycophorin A, and
acetylcholinesterase [AChE]) to cell membranes.
These proteins are likely to be absent or greatly
reduced in numbers on PNH cells. DAF protects
normal erythrocytes from complement attack.
- Hemolysis is believed to occur at night when
there is slight acidity of the blood pH, but later on
this observation was disproved. The hemolysis is
happening all throughout the day. The reason why
they call it nocturnal is that the urine tends to
concentrate at night and therefore in the morning
there is detectable hemoglobin in the testing.
- Patients may present weakness, slight jaundiced,
abdominal pain of unknown origin, and
splenomegaly. Hepatomegaly is unusual.
1.3 Bone Marrow Replacement
- Megakaryocytic precursors and cell line has been
replaced with different cells due to malignant
conditions such as:
1. Leukemia
2. Metastatic Carcinoma
3. Lymphoma
4. Plasma Cell Dyscrasia
5. Myelofibrosis
6. Granulomatous Infections
- In the Myelophthisic Thombocytopenia,
extramedullary hematopoiesis is evident the
cellular precursors are present in the peripheral
blood.
2. Abnormal Distribution
- Spleen is responsible in platelet sequestration and
destruction and making it one of the organ
responsible for thrombocytopenia.
- Hypersplenism rapid removal or destruction of
the thrombocytes even they are not yet old or
damaged. This conditions is the primary cause of
thrombocytopenia in Gauchers Disease,
Sarcoidosis, and Felty Syndrome.
- Splenomegaly there is more platelet
sequestration of the spleen which now caused the
thrombocytopenia. The spleen sequesters 50
90% instead of the normal 20%.
- The spleen contains the larger fragments of
megakaryocytes called the megathrombocytes or
large platelets, and younger thrombocytes which
are more effective in hemostasis.
3. Increase Destruction
- Platelets are lost or destroyed in the circulation
Can be divided into two:
3.1. Non-immune Mediated Destruction
3.2. Immune Mediated Destruction
3.1. Non-immune Mediated Destruction
Can be divided into two:
3.1.1. Increased Consumption
3.1.2. Miscellaneous Conditions
3.1.1. Increased Consumption
Disease associated:
3.1.1.1. Hemolytic Uremic Syndrome
3.1.1.2. Thrombotic Thrombocytopenic Purpura
3.1.1.3. Disseminated Intravascular Coagulation
3.1.1.1. Hemolytic Uremic Syndrome
- Occurs more often in children less than 8 years of
age.
- Occasionally occurs in adults with predisposing
conditions associated with endothelial cell damage.
- Endothelial damage can be caused by viral
infections, hypertension, hypoxia, and autoimmune
complexes.
- Using Western blot assay inorder to detect the
autoantibodies against cryptic endothelial antigens.
- Thrombi formation is primarily intraglomerular
with renal dysfunction proteinuria, and hematuria.

- In children, vomiting and blood diarrhea
associated with E. coli or Shigella infection
frequently occurs before the development of HUS.
- Febrile diseases maybe the antecedent symptom
in some patients.
- Some patients would appear pale and jaundiced
depending on the severity of the intravascular
hemolytic anemia.
- Purpura and bleeding from the mucous
membranes are usually present and platelet
thrombi in the kidneys lead to renal failure.
- Duration of Oliguria, blood urea levels, and
hypertension are important factors affecting
therapy and survival.
- Also occurs in adults but is much less common
than in children.
- Secondary to conditions such as pregnancy, HIV
infection, malignant hypertension, and organ
transplantation.
- Some are inherited.
- Marked poikilocytosis, schistocytosis, and
increased red blood cell distribution width are
indicators of red cell damage.
- Increased LDH 2, indirect bilirubin, and decreased
haptoglobin values are indicative of intravascular
hemolysis.
- Anemia and thrombocytopenia are usually milder.
- Indicators of impaired renal function are present.
Indicators of renal function:
1. Serum BUN level
2. Serum Creatinine
3. Serum Urea level
4. Hematuria
5. Proteinuria
6. Cylindruria
- Early diagnosis is important.
- Plasma infusion and exchange are very helpful in
treatment.
- FFPs must be infused to patients until recovery.
- Dialysis, antihypertensive, antithrombotic, and
antiplatelet drugs are also useful.
3.1.1.2. Thrombotic Thrombocytopenic Purpura
- Occurs primarily in adults with females more
affected than males.
- Platelet thrombi formation is caused by the
damage in the endothelial cells caused by viral
infections, hypertension, hypoxia, and immune
complexes.
- Using Western blot assay inorder to detect the
autoantibodies against cryptic endothelial antigens.
- Activated leukocytes release elastase, which
stimulates the endothelium to produce the very
large multimers of the vWF.
- Endothelial cell markers, TPA, and

Thrombomodulin are increased at the onset of the
syndrome.
- Thrombus formation is diffuse and affects many
organs.
- Increased levels of the very large multimers of
vWF accumulate in the patients plasma for
unknown reasons.
- As the severity progresses the very large
multimers of vWF disappear and
thrombocytopenia is observed.
- The very large multimers of vWF binds to platelets
and promote intravascular thrombus formation.
- In normal and TTP patients endothelial cells
release large to very large vWF but in normal
individuals the plasma contains a substance that
reduces the large multimers into smaller size vWF
multimers.
- Associated with preceding viral infection,
pregnancy, or drug use.
- It is diagnosed most frequently in patients
between the ages of 10 50, with a peak incidence
in the fourth decade of life.
- Fever, pallor, petechiae, neurologic
manifestations, and renal disease are the chief
clinical features.
- Neurologic manifestations, which are remittent
and subject to sudden change, include headache,
delirium, seizures, and coma.
- Neurologic problems, visual disturbance, and
abdominal pain are associated with ischemia
related to microvascular platelet thrombi.
increased red blood cell distribution width are
- Increased LDH 2, indirect bilirubin, and decreased
haptoglobin values are indicative of intravascular
hemolysis.
- Anemia and thrombocytopenia are severe.
- Hemoglobin level usually less than 10g/dL more
frequently less than 6g/dL
- Platelet count is usually less than 20X109/L
- Normal or moderately elevated BUN, creatinine,
serum potassium, proteinuria, and microscopic
hematuria.
- When patients are treated with FFP the
concentration of the very large multimers of vWF
decreases.
- Early diagnosis is of major importance to the
treatment.
- Plasma infusion and exchange are very helpful in
treatment.
- FFPs must be infused to patients until recovery.
- Anti-platelet drugs have proved to be ineffective.
- Corticosteroids and IV Ig treatment has been
unsuccessful

- FFP contains the reducing substance that is
deficient in the TTP patient.
- Platelet transfusions are to be avoided with TTP
patients because it could worsen the thrombotic
episode.
3.1.1.3. Disseminated Intravascular Coagulation
- Caused by extensive damage to vessel
endothelium or exposure to compounds that
initiate clotting like, thromboplastic substances
such as various proteolytic enzymes or tissue fluid
from damaged tissue in burns, injuries, or surgery.
- Fibrin deposition along and across the vascular
lumen, erythrocytes are fragmented or destroyed
as they are pushed through the vessel by the action
of blood pressure and rapidly following circulation.
- characterized by the widespread activation of the
clotting cascade that results in the formation of
blood clots in the small blood vessels throughout
the body.
- leads to compromisation of tissue blood flow and
can ultimately lead to multiple organ damage.
- the coagulation process consumes clotting factors
and platelets, normal clotting is disrupted and
severe bleeding can occur from various sites.
- Does not occur by itself but only as a complicating
factor from another underlying condition, usually
in those with a critical illness.
- Liver disease, HELLP syndrome, Thrombotic
thrombocytopenic purpura/Hemolytic uremic
syndrome, and malignant hypertension may mimic
DIC but do not occur via the same pathways.
DIC can occur in the following conditions:
1. Solid tumors and blood cancers (particularly
acute promyelocytic leukemia)
2. Obstetric complications: abruptio placentae, preeclampsia or eclampsia, amniotic fluid embolism,
retained intrauterine fetal demise, septic abortion
3. Massive tissue injury: severe trauma, burns,
hyperthermia, rhabdomyolysis, extensive surgery
4. Sepsis or severe infection of any kind (infections
by nearly all microorganisms can cause DIC, though
bacterial infections are the most common):
bacterial (Gram-negative and Gram-positive
sepsis), viral, fungal, or protozoan infections
5. Transfusion reactions (i.e., ABO incompatibility
hemolytic reactions)
6. Severe allergic or toxic reactions (i.e. snake or
viper venom)
7. Giant hemangiomas (Kasabach-Merritt
syndrome)
8. Large aortic aneurysms
- Thrombus formation like the TTP and HUS are
observed.
- Thrombus is found everywhere in the circulation
- the underlying cause usually leads to symptoms

and signs
- Plasmin activates the complement system and
kinin system thus the patient manifests shock,
hypotension, and increased vascular permeability.
increased red cell distribution width (RDW) are
- Increased LDH-2, indirect bilirubin, and decreased
haptoglobin values are associated with
intravascular hemolysis.
- The degree of anemia and thrombocytopenia is
dependent on the severity of the underlying
condition.
- Burr cells are absent
- Abnormal Prothrombin time (PT), activated partial
thromboplastin time (APTT), levels of coagulation
factors, D-dimers, and fibrin split products (FDPs).
- The treatment concentrates on treating first the
underlying condition.
- Transfusions of platelets or fresh frozen plasma
can be considered in cases of significant bleeding,
or those with a planned invasive procedure.
- The target goal of such transfusion depends on
the clinical situation.
- Cryoprecipitate can be considered in those with a
low fibrinogen level.
- Treatment of thrombosis with anticoagulants
such as heparin is rarely used due to the risk of
bleeding.
- Antithrombin and antifibrinolytics are generally
not used because fibrinolysis should be stimulated
inorder to remove the thrombus.
- Recombinant factor VII has been proposed as a
"last resort" in those with severe hemorrhage due
to obstetric or other causes, but conclusions about
its use are still insufficient.
3.1.2. Miscellaneous Conditions
Conditions associated:
3.1.2.1. Dilutional Loss
3.1.2.2. Contact with Artificial Surfaces
3.1.2.3. Drugs
3.1.2.4. Infections
3.1.2.1. Dilutional Loss
- Sever thrombocytopenia occurs after massive
transfusion.
- Generally it is accepted that the degree of
thrombocytopenia is directly proportional to the
number of units transfused.
- But the platelets stored in blood for more than
few days proved to be nonfunctional.
- Thrombocytopenia is correlated with increased
destruction, consumption, and platelet pool
dilution.

- This form of thrombocytopenia is of different
mechanism compared to the pregnancy induced
thrombocytopenia because pregnancy induced
thrombocytopenia is correlated to hemodilution
and increased platelet activation.
3.1.2.2. Contact with Artificial Surfaces
- Contact with cardiovascular prosthetic devices,
artificial organs, prosthetic vascular grafts, and
dialysis membrane are associated with both
quantitative and qualitative changes in platelets.
- In dialysis patients severity of the
thrombocytopenia depends on the type and
geometry of the material used in the dialysis
membrane.
3.1.2.3. Drugs
- Ristocetin, an agonist that is used in platelet
aggregation studies, was first used as an
antithrombotic until it cause thrombocytopenia in
patients by inducing in vivo platelet aggregation
- Heparin has also been implicated as causing
platelet aggregation and concomitant
thrombocytopenia.
3.1.2.4. Infections
- Sepsis-induced thrombocytopenia is a result of
direct contact of platelets invading pathogens
resulting in lysis or phagocytosis by the
reticuloendothelial system.
3.2 Immune Mediated Destruction
- Most common cause of thrombocytopenia in
patients with normal platelet production.
- Thrombocytopenia is due to immune mechanisms
that result in platelet injury and removal from
circulation.
- Antigenic determinants associated with immune
platelet destruction include: Human Platelet
Antigens (HPA) such as HPA-1a (P1a), the Major
Histocompatibility Complexes (HLA), the ABO and H
blood group system.
- Platelet-associated Immunoglobulin (PAIg) is
inversely proportional to the platelet count. (IgM)
- IgM and IgA coated platelets are destroyed in the
liver.
- IgG coated platelets are destroyed in the spleen.
Can be divided into four:
3.2.1 Isoimmune Thrombocytopenia
3.2.2 Primary Autoimmune Thrombocytopenia
3.2.3 Secondary Autoimmune Thrombocytopenia
3.2.4 Drug-Induced Immune Thrombcoytopenia
3.2.1 Isoimmune Thrombocytopenia

- Alloantigen induced to a patient who lacks the
antigen can induce immunologic response.
- Some platelet-specific alloantigens are more
immunogenic than other alloantigens.
- Platelet-specific alloantigen HPA-1a is the most
antigenic of the platelet alloantigens.
- HPA-1a is the antigen mostly associated with Post
Transfusion Purpura and Neonatal Alloimmune
Thrombocytopenic Purpura.
Disorders associated:
3.2.1.1 Post Transfusion (Isoimmune) Purpura
3.2.1.2. Neonatal Alloimmune Thrombocytopenic
Purpura
3.2.1.3. Patients Refractory to Platelet Transfusion
3.2.1.1. Post Transfusion (Isoimmune) Purpura
- A rare complication characterized by sudden,
profound, and self-limited thrombocytopenia (less
than 20X109/L).
- Bleeding occurs 2 to 12 days after the transfusion.
- Time of recovery is from 5 to 60 days.
- Most cases have been reported in women who
lacked the platelet-specific alloantigen (HPA-1a)
and who have been sensitized during pregnancy
and transfusions.
- The alloantigen is located on the platelet
membrane glycoprotein IIIa and is present in the
98% of the Caucasian population.
- The alloantibody produced is specific to P1A1
alloantigen which fixes complement in some cases.
- Plasmapheresis appears to be most effective in
resolving bleeding complications, with an increase
in the platelet count after 48 hours following
treatment.
3.2.1.2. Neonatal Alloimmune Thrombocytopenic
Purpura
- Analogous to HDFN, except that the fetal platelet
now is the target of the maternal Ig.
- Fetal platelets have a specific alloantigen
inherited from the father which is absent from the
mothers platelets.
- Thus, immunologic response against the
alloantigen is triggered.
- Occurs in the first pregnancy in 50% of the cases,
thus differentiates NATP from HDFN.
- Infants with NATP may have a generalized
petechial rash or purpura or may appear normal at
birth and develop symptoms of thrombocytopenia
within 2 3 days.
- All hematologic cells are normal except for the
platelets which may count from 30X109/L or less.
- Neonates with 50X109/L is of main concern.

- Hyperbilirubinemia may be a problem due to
excessive skin hemorrhage and frequently requires
phototherapy.
- 78% of NATP cases are mostly caused by antiHPA-1a
- 19% of NATP cases are mostly caused by antiHPA-5a
- In Asian countries presence of anti-HPA-4b
appears to be of greater importance.
- For the treatment, IgG antibodies should be
identified as autoimmune or alloimmune to select
proper treatment.
- Fetal platelet count and typing can be performed.
- If the fetus is at risk, platelet transfusion can be
administered and delivery through cesarean
section near term can be performed.
- IV-Ig administration to the mother has been
successful in elevating fetal platelet count.
- For neonates, the treatment of choice is
transfusion with either maternal platelets (washed
with ABO compatible plasma to reduce the
likelihood of further transfer of maternal
alloantibodies) or antigen-negative platelets.
3.2.1.3. Patients Refractory to Transfused Platelets
- Infusion of platelets to the patient do not produce
a sustained increase in platelet count.
- This is true to patients with aplastic anemia, or
acute leukemia, who have received long-term
platelet transfusion.
- This causes platelet alloimmunization which
causes the rapid destruction of transfused
platelets.
- The 2/3 of the antibodies produced are directed
against HLA.
- When ABO unmatched platelets are transfused,
circulating immune complexes can be formed
between the patients soluble ABH antigens and
the transfused antibodies resulting in the
destruction of platelets by the innocent bystander
mechanism.
Destruction is done through:
1. Binding of circulating immune complexes to
platelet Fc receptors
2. Binding of complement component C3 to
platelet membrane proteins.
- Anti-HPA-1a and anti-HPA-1b in the plasma of
bone marrow recipients can also cause
refractoriness to platelet transfusions.
- It is suggested the all patients who are refractory
to HLA-matched platelets be tested for plateletspecific antibodies.
- Use of HLA-matched leuko-poor platelet
concentrates may alleviate the problem for some
patients.
3.2.2. Primary Autoimmune Thrombocytopenia

(Immune or Idiopathic Thrombocytopenic Purpura)
- A well-defined autoimmune disorder
characterized by the destruction of antibodycoated platelets in the reticuloendothelial system
and by normal or increased megakaryocytic
production.
Diagnosis is made through exclusion or ruling out
other potential causes of thrombocytopenia.
- It can be either acute or chronic.
Acute ITP defined as ITP of less than 6
months.
Chronic ITP persists for more than 6
months.
- The association of acute ITP with a recent viral
illness suggests that the immune system maybe
responding to viral antigens adsorbed onto the
platelet surface or to immune complexes bound to
the platelet.
- Increased platelet-associated IgG (PA IgG) levels
are consistent.
- Autoantibodies against platelet glycoproteins IIbIIIa, and Ib-IX are mostly produced.
- Lower platelet counts have been observed in
patients with antibodies against the glycoprotein
Ib-IX.
In Acute ITP:
- occurs primarily in young children from 2
6 years of age.
- Most common cause of thrombocytopenia
in children which affects males and females
equally.
- Occurs often in the winter and spring
preceded by a viral infection.
- Up to 90% of the patients present transient
bleeding episode and a platelet count of
less than 30X109/L.
- Children with platelet count less than
10X109/L can experience severe mucosal
bleeding.
- 10% 20% of the patients may develop
chronic ITP based on the persistence of ITP
for 6 months.
- This occur in children 7 years and above.
In Chronic ITP:
- Occurs mostly in young adults ages 20 40
years who complains with
hypermenorrhagia, easy bruising,
petechiae, purpura, or prolonged bleeding
(from superficial skin cuts) that has slowly
increased in severity.
- Older patients are of greatest risk of severe
hemorrhage.
- Some patients are asymptomatic and only
detected incidentally.

- Unlike acute ITP, there is usually no
antecedent infection
- Platelet counts are usually higher than
30X109/L 100X109/L.
- Ratio of female to male prevalence is 2.2:1
- The age range is 14 78 years old.
- Aside from the platelet counts, there is increased
percentage of large platelets and increased platelet
distribution width.
- Bone Marrow examination is of value primarily to
rule out other causes of the thrombocytopenia.
- A prolonged bleeding time and abnormal clot
retraction can be attributed to the
thrombocytopenia and the binding of the
autoantibodies.
- Partial Thromboplastin time is normal.
- Increase in eosinophils, and lymphocytes has
been reported in some patients.
- Therapy is indicated when there are signs of
bleeding or the patient is at risk of hemorrhage.
- Most cases of acute ITP can be treated with
corticosteroids.
- Fastest recovery from acute ITP has been
accomplished using IV-Ig.
- Patients with chronic ITP with platelet counts
more than 50X109/L usually do not receive therapy
unless there is a risk of hemorrhage.
- They are instructed to avoid all aspirin-containing
drugs.
- Steroids or IV-Ig are commonly used as the initial
therapy.
- Splenectomy is the most effective treatment for
patients who fail to respond to the initial therapy.
3.2.3. Secondary Autoimmune Thrombocytopenia
Refers to thrombocytopenia secondary to another
disease process.
Examples of disease process:
- Chronic Lymphocytic Leukemia (CLL)
- Miscellaneous Conditions such as RA, SLE,
Crohns disease
- Infectious diseases caused by bacterial,
viral, and fungal pathogens.
- About 5% - 10% of patients with CLL and a smaller
percentage of patients with other
lymphoproliferative disorders develop immune
thrombocytopenia.
- Thrombocytopenia occurs frequently in SLE and is
almost invariably autoimmune.
- Patients with SLE have greater risk of thrombosis
than hemorrhaging.
- Splenomegaly is usual, and the bone marrow has
a larger than normal number of megakaryocytes.
- In HIV patients, Immune thrombocytopenia
appears to be a manifestation of AIDS.
- Bone marrow megakaryocytes are adequate to

increased, and PA IgG is increased.
- Unexplained thrombocytopenia in otherwise
healthy homosexual men may be an early
manifestation of AIDS.
3.2.4. Drug Induced Thrombocytopenia
- Caused by a few drugs, notably quinidine, quinine,
gold salts, sulfonamides, and their derivatives,
chloroquine, and rifampicin.
- The diagnosis is primarily based on the clinical
history of drug ingestion and exclusion of other
causes.
- The clinical history should document
thrombocytopenia while the patient is receiving
the drug and normalization of the platelet count
after the drug is discontinued.
- Patients may experience petechiae, ecchymosis,
blood-filled blisters in the mouth, and mucosal
bleeding.
- The severity of the purpura maybe
disproportionate to the degree of
thrombocytopenia, suggesting that the antibody
also damages the endothelium or induces platelet
function defect.
- Most patients recover after 7-10 days after drug
discontinuation.
- Some patients would have persistent
thrombocytopenia for 3 4 weeks may be due to
drug toxicity.
4. Preanalytic Variables
- Normal blood to anticoagulant ratio is 9:1.
- Anticoagulant used 3.4% Sodium Citrate.
- Vigorous sample shaking should avoided because
it can activate contact factor which could now
activate the coagulation cascade and consume
platelet during the process of coagulation.
- Sample should be mixed up to 8 times only.
- Traumatic phlebotomy must be avoided.
- Platelet satellitism is another sample-relate
condition that may give a falsely decreased platelet
count. This condition is the rosette formation of
platelets around the neutrophils, monocytes and
bands. This phenomenon occurs only when EDTA
samples are used. Sample must be redrawn in a
sodium citrate tube and re-analyzed.
B. Thrombocytosis
- Can be defined as the increase in the circulating
platelet count above 450X109/L.
- A large majority of patients with increased
platelet counts are reacting to stimulus.
- In Reactive Thrombocytosis, the increase in
platelet count is usually temporary, is less than
1000X109/L, and is not normally associated with

any clinical problems except for coronary bypass
surgery.
Stimuli for Reactive Thrombocytosis
1. Neoplasms
2. Inflammatory conditions
3. Iron deficiency
4. Major trauma
5. Post-splenectomy
6. post-surgery
7. epinephrine injection
8. recovery from thrombocytopenia
- Thrombocythemia is used to refer to increased
platelet count associated with chronic
myeloproliferative disorders (CMPD).
- CMPD is a group of clonal disorders which
marked thrombocytosis is found.
- Essential Thrombocythemia (ET) is characterized
by increased megakaryocyte production with a
persistent and massive elevation in platelet count.
- Reactive thrombocytosis has a platelet count of
greater than 450X109/L but less than 1000X109/L
and the increase is transitory
- Essential thrombocythemia has a platelet count
greater than 1000X109/L, which is persistent.
- Platelet morphology, variation in platelet size, and
platelet aggregation with epinephrine are typically
abnormal in thrombocythemia of CMPD bur
normal in reactive thrombocytosis.
- Increase megakaryocyte volume and leukocyte
count are typical findings in thrombocythemia in
CMPD compared to normal or decreased values in
reactive thrombocytosis.
- Reactive thrombocytosis is associated with
increases in ESR, acute phase reactants and
interleukin 6.
- In Essential Thrombocythemia these variables are
usually normal or only slightly elevated.
- No necessary treatment for reactive
thrombocytosis.
- In Essential Thrombocythemia, suppression of
megakaryocytic series is required, thus, drugs like
busulfan, hydroxyurea, recombinant interferon-,
and anagrelide are used.
Acute Phase Reactants:
1. Fibrinogen
2. VIIIC
3. VIII:Ag
4. C-Reactive protein non-specific marker of
inflammation.

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Hematology 2 Lecture Notes

Quantitative Platelet Disorders

1.1.1.2. Thrombocytopenia with Absent Radius

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