HEMATOLOGY 2 (LECTURE) PRELIMS

MODULE 3 – DISORDERS OF PRIMARY HEMOSTASIS

TOPIC OUTLINE
A. VASCULAR DEFECTS B. QUANTITATIVE PLATELET DISORDERS C. QUALITATIVE PLATELET DISORDERS
a. Connective tissue defects a. Thrombocytopenia a. Inherited Thrombocytopathy
I. Hereditary I. Decreased production I. Adhesion defects
II. Acquired II. Increased loss or destruction II. Aggregation defects
b. Alterations of vessel wall structure i. Non-immunologic III. Release defects
I. Hereditary ii. Immunologic IV. Storage pool diseases
II. Acquired III. Platelet / Splenic sequestration V. Granule-release defects
c. Vascular damage b. Thrombocytosis b. Acquired Thrombocytopathy
I. Infectious purpura I. Primary Chronic Thrombocytosis I. Drugs
II. Autoimmune vascular purpura II. Reactive II. Diet
d. Miscellaneous abnormalities causing purpura secondary to vessel damage III. Diseases

A. VASCULAR DEFECTS
VASCULAR DEFECTS

 Categorized into HEREDITARY and ACQUIRED DEFECTS causing bleeding secondary to vascular abnormalities of different types
 CONNECTIVE TISSUE DEFECTS (Refer to Table 2A)
o Found in all three layers of the vessel wall; thus, hereditary connective tissue defects affect vessels in all three layers of their structure

TABLE 1. VASCULAR DEFECTS

ABNORMALITY HEREDITARY ACQUIRED

Connective tissues (Refer to Table 2A) Ehlers-Danlos Syndrome Vitamin C deficiency (Scurvy)
Pseudoxanthoma Elasticum Senile purpura
Corticosteroid purpura
Cushing disease

Altered blood vessel wall structure (Refer to Table 2B) Hemorrhagic telangiectasia Diabetes mellitus
Cavernous hemangioma (Kasabach-Merritt Syndrome) Amyloidosis

Vascular damage Infectious purpura

Autoimmune vascular purpura

Miscellaneous abnormalities causing purpura secondary to BV damage Waldenstrom’s macroglobulinemia

Kaposi’s sarcoma
Certain skin disease
Hemochromatosis
Snake venom

TABLE 2A. CONNECTIVE TISSUE DEFECTS

HEREDITARY CONNECTIVE TISSUE DEFECTS
CONDITION INHERITANCE DESCRIPTION CAUSE MANIFESTATIONS DX / Pr / Tx / Lab results

Ehlers-Danlos Autosomal  Problem: DEFECTIVE  Gene alterations: (discussion)  Hypermobile joints (image A) and Dx:
Syndrome dominant (AD) COLLAGEN SYNTHESIS o Problems with the production of fibrillar hyperextensible skin (C, D)
 Affects the CT of the skin, collagen / collagen fibrils o Can be stretched much  s/s
Autosomal  vasculature, and bones  lead o Collagen-modifying or collagen-processing more than normal skin,  Results of physical examination
non-sex genes to lack of structural tissue enzymes but returns to normal on  Genetic testing (checking for
support and great tissue  Digesting, rearranging of collagen in release alterations)
Dominant  fragility order for them to be biologically active o Increase in tissue
needs only a  Enzymes that modify GAGs within elasticity Pr & Tx:
single copy from the ECM  Hemorrhagic tendencies (skin or
mucous membranes)  No known therapy / cure

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either of the  Brought about by defects that lie in: (module) o Skin ecchymoses  Most have normal lifespan
parent o PEPTIDASE ENZYME  converts procollagen o Hematomas
to collagen o Bleeding from the
o PROCOLLAGEN itself gums
o CROSS-LINKING OF MATURE COLLAGEN  Excessive postpartum
bleeding
 GIT bleeding
 Prone to bruise formation
 Higher tendency to scar (B)
o Wound healing requires
functional collagen
 Raynaud’s phenomenon (image on the right)
o Distal part of the hands are pale due to decreased blood flow
and BV dilation
o From pale (A)  blue (B)  red (C)

Pseudoxanthoma Autosomal  The ELASTIC FIBERS of the  Mutations in ABCC6 gene  Common manifestation: Easy Dx:
Elasticum recessive (AR) skin are abnormal  causes the o ABCC6: synthesis of elastin (elastin fiber bruisability and hemorrhagic episodes
skin to lax abnormal) (tendency for the BV to become easily  s/s
aka Gronblad- Recessive   CT elastic fibers in small damaged)  Results of physical examination
Strandberg requires copy arteries:  Most common causes of death:  Results of skin biopsy
Syndrome from both o Calcified Subarachnoid and GIT bleeding  Eye examination
parents in order o Structurally and  Ectopic mineralization and fragmented
for it to be functionally abnormal elastic fibers of the CT of the skin, Pr & Tx:
apparent retina, and vascular walls
o Deposition of minerals, oftentimes calcium, in abnormal places  Lab tests do not provide
in the body diagnosis
o Mineralization is also present in the eyes (retina)  No known therapy / cure
o BV calcification  Complications may limit lifespan
 BV stiffens  difficulty in constriction and dilation
 Affected areas of the body: neck, axillary, groin
o Skin usually thickens, loose, grooved, inflexible (image on the
right)

ACQUIRED CONNECTIVE TISSUE DEFECTS

CONDITION DESCRIPTION CAUSE MANIFESTATIONS DX / Pr / Tx / Lab results

Vitamin C VITAMIN C  Dietary deficiency of Vitamin C (ascorbic acid)  Gingival (gum) bleeding (C) Tx:
Deficiency  In the absence of Vit C: o Visibly thicken
(Scurvy)  Required for the formation of intact, stable collagen, o There is deficiency of the intercellular cement o Red-purple coloration  Administration of ascorbic
particularly in BVs substances that holds endothelial cells together  Coiled hairs acid
o Hydroxylation of PROLINE and LYSINE o “cork-screw” o Usually brings the
cannot take place  no collagen production appearance plasma level of Vit C
o Collagen cannot be formed properly  Bleeding tendencies and the vascular
 Causes fragility and serious bleeding o Ecchymoses and integrity back to
problems purpura normal
 Other conditions that may cause scurvy: o Hemorrhage into o Rapidly eliminates the
o Pregnancy subcutaneous tissues hemorrhagic
o Breastfeeding and muscles manifestations
o An overactive thyroid gland o Petechiae (often
(hyperthyroidism) develop on the thighs Lab results:
o Prolonged diarrhea and buttocks, particularly around the hair follicles
 BT and coagulation tests 
o Surgery (PERIFOLLICULAR PETECHIAE)) (A, B, D)
usually normal
o Burns o Large hemorrhagic areas may develop just below the eyes,
o Smoking particularly in affected infants  Tests for plt function 
sometimes abnormal

Senile Purpura  Senile: relates to all age  Progressive degeneration and loss of collagen,  Red to purple ecchymotic spots on the
 Benign, acquired, and chronic disorder of the elderly elastin, and subcutaneous fat due to aging forearm and on the back of the hands, and
 There may also be a defective cross-linking of collagen neck (secondary to loss of skin and vascular
elasticity)
o The hemorrhage resolves but the
area retains a permanent brownish
color
 This is possibly because
the Hgb is not properly
removed by the aging
macrophage system
(degenerated)

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Steroid /  Atrophy of collagen fibers due to chronic steroid  Chronic exposure to steroids
Corticosteroid use
Purpura  STEROIDS
o Inhibits response of macrophages
o Bleeding  cannot be engulfed by
macrophages

Cushing Disease  Involves the endocrine system: pituitary gland  Adrenals overproduce corticosteroids  Skin becomes thin
affects adrenal gland  Bruises easily
 Heals poorly when bruised or cut
 Striae (image on the right)
o Differentiate if it is caused by
Cushing disease or
pregnancy
 Check first if the px
is pregnant
 Check hormonal panel

TABLE 2B. ALTERATIONS OF VESSEL WALL STRUCTURE

HEREDITARY ALTERATIONS OF VESSEL WALL STRUCTURE
CONDITION INHERITANCE DESCRIPTION CAUSE MANIFESTATIONS DX / Pr / Tx / Lab results

Hereditary AD  Gr. Telangiectasia: telos  end;
Hemorrhagic angeion  BVs; ektasis 
Telangectasia dilation or widening
o Small widened BVs
aka “Osler-Weber-  Characterized by bleeding that
Rendu Syndrome” occurs from TELANGECTASIAS
–vascular malformations of
thin, dilated small vessels in
the skin and mucosae
 The small blood vessels are
focally disorganized and
dilated throughout the body, their
wall support is poor, and their
ability to contract is diminished
o Thus, any trauma to the
vessels causes them to
bleed readily and for a
prolonged period
 May be detected in childhood
 Bleeding usually begins during
the 2nd or 3rd decade
 Genetic mutations that involve signaling of TGF-β  LESIONS Tx:
o A transformative / transforming group factor o Pinpoint (0.3 mm)
o Affects cell cycle, apoptosis, certain cell o Red to violet  Given only based on symptoms
signaling processes, and proliferation of certain o Raised or flat  Iron therapy
cells o Round or spider-like (1st  Therapeutic drugs and
image) surgical techniques (may be
o May bleed spontaneously required to stop or prevent
or from minor trauma bleeding episodes)
o Appear most commonly on
the face, lips, tongue,
mucous membranes of
the mouth and nose,
ears, conjunctivae, and
palms of the hands and
soles of the feet
o Permanent
o Number increases with advancing age
 Most common symptoms: Epistaxis and alimentary bleeding
 Iron deficiency
anemia (if
chronic)
 Dilated
capillaries on
skin and
mucosal
membrane
 Arteriovenous
alterations

Cavernous AD  Cavernous  cave-like; hema   Spontaneous  Cavernous or “strawberry” (red-blue color)  The tumor requires surgical
Hemangioma blood; oma  swelling hemangioma (1st image) removal
 Tumor
aka Kasabach- o A tumor that encloses large vascular
Merritt Syndrome spaces and it is partly or completely
filled with blood (2nd image)
o Present at birth or soon thereafter
o Composed of soft
vascular
malformations
that commonly
swell and bleed
at the surface
o Size: small to
enormous
lesions that protrude from the skin surface

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o Formation of fibrin clots, plt consumption, and red cell

destruction secondary to vascular obstruction occur at the
site of the tumor
 Thrombocytopenia
 Microangiopathic Hemolytic Anemia (MAHA)
o Involves smallest BVs
o Destruction of RBCs
 Consumptive coagulopathy
o Decrease in fibrinogen concentration (hypofibrinogenemia)
 Presence of endothelial cells, spindle cells, and abnormal lymphatic
tissues

ACQUIRED ALTERATIONS OF VESSEL WALL STRUCTURE

CONDITION DESCRIPTION

Atherosclerosis  Under DYSLIPIDEMIA  build-up of lipids, especially cholesterol, in the BVs (arteries)
 Plaque  eventually becomes ATHEROMA that will slough off and will block the heart

Diabetes mellitus  Metabolic disorder that affects how glucose will be taken into the cell
 Involvement of inflammatory mediators  affects the integrity of the BVs  may lead to thrombosis, fibrosis, and bleeding tendencies
 Large BVs become ATHEROSCLEROTIC and the capillary basement membrane may thicken  blocking the normal blood flow

Amyloidosis  There is abnormal deposition of FIBRILLAR PROTEINS (AMYLOID)  obstruct the function of many organs including the vascular system
 Weakens the vessels and causes hemorrhaging

B. QUANTITATIVE PLATELET DISORDERS

a. THROMBOCYTOPENIA

 Defined as a plt count less than 140x109/L and occurs whenever the plt production is insufficient to meet the need
 2 MAJOR CAUSES:
o Rate of production is decreased
o Rate of plt loss is increased
 The severity of bleeding is related to the degree of thrombocytopenia (Refer to Table 3)

TABLE 3. SEVERITY OF BLEEDING AND DEGREE OF THROMBOCYTOPENIA

PLATELET COUNT / FUNCTION DEGREE OF THROMBOCYTOPENIA
Less than 100x109/L Bleeding time is INVERSELY PROPORTIONAL to the platelet count
Above 50x109/L; plt fxn is normal Pxs will have no hemorrhagic symptoms unless subjected to trauma or surgery
Less than above 50x109/L Referred to as SEVERE THROMBOCYTOPENIA
Less than 20x109/L Spontaneous bleeding occurs
Normal plt fxn The template BT is usually within the normal range as long as plt counts are greater than 100x109/L (when the plt count falls below
this, the degree to which BT is prolonged is INVERSELY PROPORTIONAL to the decrease in plt count);
Plt aggregation studies should be normal
Below 60x109/L Clot retraction is usually abnormal
DEGREE OF THROMBOCYTOPENIA
NORMAL 150-400 x109/L
MILD 100-150 x109/L
MODERATE 50-99 x109/L
SEVERE <50 x109/L

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TABLE 4. LABORATORY MEASUREMENT OF PLATELET COUNT

AUTOMATED HEMATOLOGY CELL ANALYZER ERRORS (SPURIOUS CELL COUNTS)

 Coulter principle  Sample clotting  problem with specimen collection

 Manual counting is still needed for plt estimation  Spontaneous plt agglutination
o Cold Autoimmune Hemolytic Anemia
MARROW ASPIRATE OR BIOPSY o Platelet Satellitosis
 Plt binds to surface of WBC (neutrophils)
 Aspirate: BM cells in the bone  Pseudothrombocytopenia
 Biopsy: fragment of bones  Use citrate or heparin
 Purpose: assess plt production or destruction  HOW TO KNOW: establish thrombocytopenia, validate the results of blood smear by blood film, recollect
 Check for hematopoietic disease processes and evaluate the number and appearance of megakaryocytes if using different anticoagulant
o Binding to WBCs

TABLE 5. CLASSIFICATION OF THROMBOCYTOPENIA

Megakaryocyte hypoproliferation: Aplastic anemia, Drug toxicity, Alocohol toxicity, Viral infection, Congenital states
DECREASED PRODUCTION: Ineffective thrombopoiesis: Megaloblastic anemia, Paroxysmal Nocturnal Hemoglobinuria (PNH), Thrombopoietin deficiency, Ethanol abuse without malnutrition, Severe iron-deficiency anemia, Viral
(Refer to Table 6A) infection
Marrow replacement: Leukemia, Plasma-cell dyscrasia, Metastatic carcinoma, Myelofibrosis, Lymphoma, Granulomatous infections
Non-immunologic (due to intravascular coagulation and Loss: Severe hemorrhage, Extensive transfusion
increased platelet clearance) Consumption: DIC, HUS, TTP, Foreign surface, Thermal injury, Sepsis without DIC
INCREASED LOSS OR DESTRUCTION: (Refer to
Isoimmune: NATP, PTP, Refractory to platelet syndrome
Table 6B)
Immunologic Autoimmune: ITP, Disease-associated
Viral infection
SPLENIC SEQUESTRATION (Refer to Table 6C)

TABLE 6A. THROMBOCYTOPENIA: DECREASED PLATELET PRODUCTION

INHERITED MEGAKARYOCYTIC HYPOPLASIA
CONDITION INHERITANCE DESCRIPTION CAUSE MANIFESTATIONS DX / Pr / Tx / Lab results

Fanconi Anemia AR  Characterized by marked  DEFECTIVE dsDNA REPAIR  Most notable skeletal deformities: absent or
(FA) hypomegakaryocytic  Most common cause of inherited BM failure hypoplastic thumbs and short stature
thrombocytopenia,  Pancytopenia
skeletal deformities, and  Microcephaly  small brain and head
sexual and mental  Prone to dislocated hips
retardation

Thrombocytopeni AR  Not well established  Transient thrombocytopenia

a with Absent  Neonates with TAR present at birth with severe thrombocytopenia and normal RBC and
Radius (TAR) WBC count
 Defect exists at the stem cell level and involves early progenitors of all cell lines
 Most evident abnormality: bilateral absence of the forearm bones (radius)
 The defect affects only the megakaryocyte progenitor cells
 Up to 90% of the neonates with TAR die in the 1st year of life
o There is a possibility that the plt count will be close to normal by 5-6 years of age
 Mental retardation occurs in about 7% of the TAR neonates  associated with
INTRACRANIAL HEMORRHAGE
 Cow’s milk intolerance  exacerbates thrombocytopenia when px drinks cow’s milk

Amegakaryocytic  Differs from TAR in that the

Thrombocyto- thrombocytopenia
penia (AMT) persists and the px
deteriorates
 In some cases, there is
complete failure of the
marrow  affects all
hematopoietic cell lines

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ACQUIRED MEGAKARYOCYTIC HYPOPLASIA

(MARROW DAMAGE  failure in plt production; possible that all aspects of normal hematopoiesis are decreased  MARROW APLASIA)
(RADIATION THERAPY, CHEMOTHERAPY, EXPOSURE TO TOXIC CHEMICALS AND ALCOHOL, COMPLICATION OF VIRAL INFECTION  reduction in marrow megakaryocyte)

CONDITION DESCRIPTION

Aplastic anemia  Can be a consequence of toxic chemical or physical agents

o IONIZING RADIATION and CHEMOTHERAPEUTIC AGENTS  produce a dose-dependent suppression of cells at the stem cell level
 Viral infections  implicated in bone marrow hypoplasia
 Drugs: CHLOROTHIAZIDE, CISPLATIN and CARBOPLATIN, and ANAGRELIDE  directly suppress megakaryocyte production

Myelophthisic  Refers to the crowding out of megakaryocytic precursors by space-occupying lesions in the marrow
Thrombocytopenia  Invasion of the marrow by non-megakaryocytic tissues occurs in many conditions such as:
o Myelofibrosis
o Metastatic tumor
o Leukemia
o Hodkin and non-Hodgkin lymphomas
o Microangiopathic Hemolytic Anemia (MAHA)
o Osteopetrosis

Prolonged Hypoxia  Reduces the pool of megakaryocytic thrombocytopenia by reducing the pool of committed megakaryocyte progenitor cells by means of a greatly expanded erythroid progenitor pool

INHERITED INEFFECTIVE THROMBOPOIESIS

CONDITION INHERITANCE DESCRIPTION CAUSE MANIFESTATIONS Dx / Pr / Tx / Lab results

May-Hegglin AD  Characterized by Dohle bodies
Anomaly within leukocytes, a variable
degree of thrombocytopenia and
giant plts
 Thrombocytopenia is attributed to
ineffective thrombocytosis with
the possibility of an immune
involvement of destruction
 Mutation in a gene causing defective  Often symptomatic  Degree of
megakaryocytic maturation thrombocytopenia:
9
20-120x10 /L
 MPV: 15-20 fL
 Plt fxn: normal

Bernard Soulier AR  Causes plt adhesion defect   Larger DMS in megakaryocytes  abnormally large
Syndrome leads to bleeding problems in proplatelet tips
affected individuals
 Deficiency of the
GLYCOPROTEIN Ib/IX in plts

Wiskott-Aldrich  An immunodeficiency syndrome  Mutation in the WASP gene  Small plts

Syndrome  Characterized by severe  Thrombocytopenia
thrombocytopenia and  Decreased α-granules and dense bodies
excessively small plts  lead to  Eczema
bleeding  Recurrent infections

Paris-Trousseau  Characterized by  Skull dysmorphism  Although plts in

Syndrome thrombocytopenia due to  Developmental delay peripheral circulation
ineffective thrombopoiesis and  Multiple organ abnormalities have normal life
production of span, 15% of the plts
micromegakaryocytes in the BM in peripheral blood
show giant α-
granules resulting
from the fusion of α-
granules

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ACQUIRED INEFFECTIVE THROMBOPOIESIS

Normal to increased number of certain BM cells; BM cells are dysplastic; generalized cytopenia; associated with Vitamin B12 deficiency (megaloblastic anemia)  possibility of increased apoptosis of developing megakaryocyte

CONDITION DESCRIPTION CAUSE MANIFESTATIONS Dx / Pr / Tx / Lab results

Ethanol abuse  Suppresses thrombopoiesis at the level of the  Defective formation and decreased lifespan
maturing megakaryocyte  decreases the plt
lifespan
 Plt counts usually start to increase after 2-5 days of
abstinence from alcohol

Vitamin B12 or  Results in an impairment of DNA synthesis  leads to  Due to short lifespan of plts, Vit B12-deficient pxs present with mild thrombocytopenia
Folate Deficiency dyspoiesis and megaloblastic transformation of cells before the RBC megaloblastic changes are seen
in the myeloid series

Paroxysmal  Affects the hematopoietic stem cells  Thrombocytopenia is primarily caused by  Presence of Hgb in urine
Nocturnal  Cells have enhanced susceptibility to complement ineffective thrombopoiesis
Hemoglobinuria binding and lysis  Megakaryocyte progenitors have
(PNH) decreased proliferative activity

Viruses  Invade megakaryocytes  leads to decreased plt

production
 They can impair megakaryopoiesis by interacting at
the cell surface or thru viral entry and intracellular
replication
 Viruses known to invade megakaryocytes include the ff:
o Hepatitis C
o Herpes simplex
o HIV
o Colorado tick fever

TABLE 6B. THROMBOCYTOPENIA: INCREASED LOSS OR DESTRUCTION

NON-IMMUNE PLATELET DESTRUCTION: PLATELET CONSUMPTION
CONDITION DESCRIPTION CAUSE MANIFESTATIONS LAB RESULTS

Disseminated  Toxins or conditions that trigger procoagulant  Massive tissue damage  Thrombocytopenia
Intravascular release  G-septicemia  Schistocytes
Coagulation (DIC)  Obstetric complications  1 or 2 clotting factors and
Three major
 Organ destruction inhibitors
conditions
 Severe transfusion reactions  FDPs
characterized by
 tumors  D-dimer
non-immune
thrombocytopenia
due to increased
Hemolytic Uremic  In the early stages of HUS, thrombi formation  Damage to endothelium  Hematologic studies
plt consumption
Syndrome (HUS) is primarily intraglomerular  Thrombotic microangiopathy  Hemolytic workup
and shortened plt
 Common manifestations: renal  RBC fragmentation  UA
lifespan
dysfunction, proteinuria, and hematuria
Thrombocytopenia Both HUS and TTP
results from either have a common
Thrombotic  Can be congenital w/ unknown etiology (1/3-1/2,  PENTAD (FATRN) Considered sufficient for dx:
acute or chronic pathomechanisms  Thrombus formation is diffuse and affects
Thrombocytopenic most) o F  Fever
activation of the involving endothelial many organs 
Purpura (TTP)  Can be pregnancy-related o A  Anemia (MAHA) Anemia and
coagulation cell damage   Increase levels of vWF multimers T  Thrombocytopenia thrombocytopenia
system and the  Can be a result of marrow transplantation o
causes plt thrombi to accumulate in the plasma for unknown 
 Can be a result of drug therapy- as an effect of o R  Renal pathology (oliguria, Schistocytosis
generation of form: reasons
inhibitor mediated cleaving protease deficiency; hematuria, ESRD)  Increased LDH
thrombin  As the severity of TTP progresses, these o N  Neurological symptoms
tacrolimus, cyclosporine; quinine
large multimers disappear and the plt
 Secondary to plt activation, aggregation, and (hemiplegia, aphasia,
count decreases paresthesia, visual disturbance)
thrombus formation

HELLP Syndrome  HEMOLYSIS, ELEVATED LIVER ENZYMES, AND LOW PLATELETS (HELLP) SYNDROME  Result from microvascular endothelial activation  Coagulation studies:
and cell injury normal PT, 50% may
have prolonged APTT
 Hemolytic workup (PBS)

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NON-IMMUNE PLATELET DESTRUCTION: MISCELLANEOUS

CAUSE DESCRIPTION

Dilutional Loss  Severe thrombocytopenia is a common occurrence following massive blood transfusions
o Degree of thrombocytopenia is DIRECTLY PROPORTIONAL to the number of units transfused
 The number of functional plts in blood that have been stored for more than a few days is close to zero
o Thus, the pxs requiring extensive transfusions develop thrombocytopenia by acute blood loss, plt consumption, and dilution of their own plt pool

Artificial Surfaces  Plt contact with artificial surface such as vascular prosthetic devices, artificial organs, prosthetic vascular grafts, and dialysis membranes is associated with quantitative and qualitative changes in plt function

Drugs  Drug-induced plt clumping can result in thrombocytopenia

 Among the drugs implicated in this mechanism are RISTOCETIN and HEPARIN

Infections  SEPSIS-INDUCED THROMBOCYTOPENIA  can result from the direct interaction betw the organism and plts, resulting in lysis or phagocytosis by the RES

IMMUNE PLATELET DESTRUCTION: ISOIMMUNE THROMBOCYTOPENIA

CONDITION DESCRIPTION CAUSE MANIFESTATION LABS

Neonatal PLATELET-SPECIFIC  Homologous to HDFN,  Measurement of mother’s plasma

Alloimmune ALLOANTIGEN HPA-1a except that plt is the  Specificity for neonate’s plts
Thrombocytopenic target of the maternal
Purpura (NATP)  The most IgG
antigenic of the plt
alloantigens
Post-transfusion  Associated with  A sudden, profound,  Alloimmunization  Sudden, severe thrombocytopenia after 5-10 days
(Isoimmune) NATP and PTP and self-limited against platelet
Purpura (PTP) thrombocytopenia antigens
caused by sensitization
of Ab response by an
alloantigen located on
the membrane
glycoprotein IIIa

Refractory to Platelet  Pxs refractory to plt transfusion develop thrombocytopenia by not producing sustained increase in plt count
Syndrome  Among pxs with APLASTIC ANEMIA or ACUTE LEUKEMIA who have received long-term plt support, plt alloimmunization causes a rapid destruction of transfused plts

IMMUNE PLATELET DESTRUCTION: AUTOIMMUNE THROMBOCYTOPENIA

CONDITION DESCRIPTION / CAUSE MANIFESTATIONS Dx / Pr / Tx / Lab results

Primary  IMMUNE THROMBOCYTOPENIC PURPURA (ITP) ACUTE ITP ACUTE ITP

Autoimmune o haracterized by the destruction of antibody-coated plts in the RES and by normal to increased megakaryocytic
Thrombocytopenia production  Affects adults of age 20-40  Plt count: less than 20x109/L
o Loss of immunological tolerance to autoantigens on px’s own plts (IIb-IIIa and Ib-IX) o Manifestations:  Tx: IV immunoglobulin (Anti-D antibody), interferon, and
o Cause is related to drugs and infection hypermenorrhagia, cyclosporin
o Purpura, menorrhagia, epistaxis, gingival bleeding, retinal hemorrhages, bruising tendency easy bruising,
 Autoantibodies target membrane glycoproteins IIb-IIIa and Ib-IX petechiae, purpura, CHRONIC ITP
o The binding of autoantibodies to plts can cause phagocytosis by the immune system by an Fc receptor mechanism and or prolonged
activation of the complement pathway  allows more efficient phagocytosis bleeding from  Plt count: 30-80x109/L
superficial skin  Tx:
cuts o Steroids and IV immunoglobulin (initial therapy)
o Splenectomy  most effective management
CHRONIC ITP among pxs who do not respond to initial tx

 Affects older adults

Secondary  Refers to thrombocytopenia that is secondary to another disease process

Autoimmune  Disease that lead to thrombocytopenia include the ff:
Thrombocytopenia o Lymphoproliferative disorders (e.g., chronic lymphocytic leukemeia (CLL), and Hodgkin disease)
o Miscellaneous conditions (e.g., rheumatoid arthritis, SLE, and Chron’s disease)
o Infectious diseases caused by bacterial infections, HIV, and other viruses

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IMMUNE PLATELET DESTRUCTION: DRUG-INDUCED

CONDITION DESCRIPTION / CAUSE MANIFESTATIONS Dx / Pr / Tx / Lab results

Drug-induced  Drugs implicated to cause immune thrombocytopenia include:  Common manifestations:  Plt count returns to normal limit 7-10 days after drug is
Immune o Quinidine o Sudden onset of discontinued
Thrombocytopenia o Quinine petechiae
o Gold salts o Ecchymoses Dx:
o Sulfonamides and their derivatives o Blood-filled blisters
o Chloroquine in the mouth  1) exposure to the candidate drug preceded
o Rifampicin o Mucosal bleeding thrombocytopenia
 The Ab is directed against either a drug-platelet complex or a drug-plasma protein complex that binds to the plt, or there could  2) recovery from thrombocytopenia was complete and
also be a drug-induced synthesis of plt autoantibody sustained after discontinuing the candidate drug
 3) other causes for thrombocytopenia were excluded

TABLE 6C. THROMBOCYTOPENIA: SPLENIC SEQUESTRATION

Platelet  SPLEEN  responsible for thrombocytopenia by increased phagocytosis and destruction of damaged plts or by increased sequestration of normal, undamaged plts
Sequestration  This happens in HYPERSPLENISM caused by the ff:
o Gaucher disease
o Sarcoidosis
o Felty Syndrome

b. THROMBOCYTOSIS

 Defined as an increase in plts above 450x109/L

 Classified into 2: reactive and essential (Refer to Table 5)

TABLE 7. CLASSIFICATION OF THROMBOCYTOSIS

REACTIVE THROMBOCYTOSIS ESSENTIAL THROMBOCYTOSIS

 Caused by a stimulus (e.g., neoplasma, inflammatory conditions, iron deficiency, major trauma, post-splenectomy, post-  A condition characterized by extensive thrombocytosis due to increased megakaryocyte production with persistent and
surgery, epinephrine injection, or recovery from thrombocytopenia) massive elevation in plt count
 Increased plt count is temporary, and is less than 1000x109/L and is not associated with any clinical problems
THROMBOCYTHEMIA

 A term that refers to increased plt counts associated with chronic myeloproliferative disorders (CMPD)

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REACTIVE: PRIMARY CHRONIC THROMBOCYTOSIS:

 Physiologic  Essential thrombocythemia

 Iron Deficiency Anemia  Polycythemia vera
 Rapid Blood Regeneration: Acute blood loss, Hemolytic anemia, Rebound Postoperative  Chronic granulomatous leukemia
 Infections and inflammatory diseases  Myelofibrosis with myeloid metaplasia
o Chronic Disorders: Tuberculosis, Ulcerative colitis, sprue, rheumatoid arthritis, osteomyelitis
o Acute Infections
 Neoplasms: Carcinoma, Hodgkin disease

TABLE 8. TYPES OF THROMBOCYTOSIS

CONDITION DESCRIPTION CAUSE
Can be caused by essential thrombocythemia, polycythemia vera, and chronic myelocytic leukemia
Primary  Uncontrolled, malignant proliferation of plts
Thrombocytosis

Secondary  Increased plt production  Chronic and acute inflammatory disease

Thrombocytosis  Plt count is elevated, but <1000x109/L  Iron deficiency: Iron regulates thrombopoiesis by inhibiting thrombopoietin; deficiency causes increased TPO
 Rapid blood regeneration due to hemolytic anemia and acute blood loss
 Exercise
 Other conditions: Cytotoxic drug withdrawal
 Neoplasms

C. QUALITATIVE PLATELET DISORDERS

TABLE 9A. QUALITATIVE PLATELET DISORDERS: INHERITED THROMBOCYTOPATHY
ADHESION DEFECTS
Extremely rare
Defect in the Ib molecule: receptor sites for thrombin mediates adhesion of platelets to the BV wall by binding vWF

CONDITION DESCRIPTION CAUSE MANIFESTATIONS Dx / Pr / Tx / Lab results

Bernard-Soulier  Abnormal bleeding occurs because plts lack  Mild to moderate thrombocytopenia (not very common)  MPV of giant plts: 12.5 fL
Syndrome (BSS) the vWF adhesion receptor GP Ib-V-IX that  Marked anisocytosis of plts (evident)  majority of them being as big  BT: excess of 20 minutes
is necessary for binding as lymphocytes  Decreased plt retention by glass bead
 Plt lifespan shortened to 4 days columns
 Epistaxis  Plt count: very low to low normal
 Gingival bleeding  Plt aggregation studies: reduced
 Cutaneous bleeding  Abnormal ristocetin plt agglutination
 Hemorrhage associated with trauma

Platelet-type  Aka PSEUDO VON WILLEBRAND DISEASE  BT: prolonged

(Pseudo) von  Characterized by abnormally enhanced binding of  Plts show hypersensitivity to ristocetin
Willebrand Disease vWF to the plt GP Ib-V-IX membrane receptor 
results to the loss of vWF from the plasma and the
removal of vWF-bound plts from the circulation

AGGREGATION DEFECTS

Glanzmann  A thrombocytopathy associated with a defect in the GP  Inability of fibrinogen to bind w/ plts  Plts are normal in number, size,
Thrombasthenia IIb-IIIa complex  Lack of thrombasthenin/actomyosin morphology and prolonged
(GT) causes clot retraction defect  Plts do not aggregated with ADP,
TYPE I GT epinephrine, collagen, or thrombin,
but will react with ristocetin
 Lacks the GP IIb-IIIa as well as intraplatelet fibrinogen
 thus, plts cannot perform clot retraction

TYPE II GT

 Plts contain subnormal levels of fibrinogen and

decreased amounts of GP IIb/IIIa (15% only)

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RELEASE DEFECTS: STORAGE POOL DISEASES (characterized by abnormal release of ADP secondary to lack of α- or dense-granules; there may also be a deficient quantity of ADP stored within the granules)

Gray Platelet  α-granules are lacking  Lifelong history of mild bleeding, easy bruising, moderate  Wright-stained PBS: plts appear to be
Syndrome thrombocytopenia, and abnormal plt morphology larger and gray to blue-gray in color
 Tests for the constituents of α-
granules are abnormal

Wiskott-Aldrich  An immunodeficiency disorder  The profound thrombocytopenia is brought  Prone to hemorrhage and recurrent infections  Plts are significantly small, almost 2/3
Syndrome  Characterized by small plts and the TRIAD OF: about by rapid plt turnover and ineffective of the normal size
o THROMBOCYTOPENIA production  MPV: significantly reduced
o RECURRENT INFECTIONS  Abnormal cellular membranes (due to
o ECZEMA lack of surface proteins)
 Decreased α-granules and dense bodies

Hermansky-Pudlack  Characterized by a TRIAD OF:

Syndrome o TYROSINASE-POSITIVE
OCULOCUTANEOUS ALBINISM
o ACCUMULATION OF CEROID-LIKE
PIGMENT IN MACROPHAGES
o BLEEDING TENDENCY ASSOCIATED WITH
ABNORMAL PLT FXN
 Associated with the lack is dense bodies, while the
number of α-granules is normal

RELEASE DEFECTS: GRANULE-RELEASE DEFECTS (characterized by impaired secretion of normal granule contents, referred to as ASPIRIN-LIKE DEFECT)

Deficiency of Platelet  Include deficiencies in the cyclooxygenase and

Prostaglandin abnormal TXA2 activity  leads to abnormal plt
Enzymes aggregation

Cyclooxygenase  Mild bleeding disorder  Pxs are advised to avoid anti-platelet

Deficiency drugs

TABLE 9B. QUALITATIVE PLATELET DISORDERS: ACQUIRED THROMBOCYTOPATHY

DRUGS
DRUG CAUSE AND EFFECT

Aspirin  Pxs taking aspirin have abnormal aggregation due to the inhibition of cyclooxygenase

Indomethacin,  Have the same effects as to aspirin

Ibuprofen,
Butazolidine

Carbenicillin  Affects plt function by interacting with glycoproteins on the surface of the platelet  causes reduced response to aggregating agents

Alcohol  Prolonged exposure to alcohol impairs PF3 release and reduces aggregation due to the inhibition of TXA2

Dipyridamole  Can increase plt cAMP concentration  inhibit plt function

IV Dextran and  Reduce plt function because of the plt surface coating action of these expanders
related plasma
expanders

DIET

Fish  Significant amounts of fish in the diet can decrease plt function
 This is brought about by the replacement of arachidonic acid production with the fatty acids present in fish oils and the production of inactive prostaglandin

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Herbs  Herbs used in Szechwan cooking decreases plt release reaction

Onions, garlic, and  Contain substances that can inhibit plt aggregation
related plants

Vitamin B12 or  May lead to qualitative plt defects as well as thrombocytopeni

Folate Deficiencies

Large amounts of  Affect plt lipids through peroxidation with resulting defects in prostaglandin synthesis
Vitamin E

DISEASES

Myeloproliferative  Malignant myeloproliferative disorders are associated with large, hypogranular platelets that can be defective in any or all functions that reflect fundamental defects in megakaryocyte maturation
Disorders

Uremia  An increase in BUN is associated with qualitative plt defects that can be corrected with dialysis
 Presentations include decreased adhesion, aggregation and defective release caused by the metabolites of urea – GUANIDOSUCCINIC ACID and PHENOLIC ACID  inhibit platelet aggregation
 Some patients exhibit defective factor VIII/vWF complexes

DIC  Prematurely activated plts release granules causing an acquired platelet SPD
 The fibrin(ogen) degradation products that circulate in DIC interact with platelet membranes  inhibit adhesion or aggregation

Immunoglobulin  Antibody binding to plts accelerates platelet destruction and inhibits platelet function
Production  The reduced platelet aggregation using collagen, ADP, and epinephrine seen in SLE and ITP has been associated with increased levels of immunoglobulins
 Antibodies such as anti-HPA-1a which binds to GP IIIa can bind to membrane receptors and inhibit platelet function while some can affect the uptake of substances into the platelet granules during megakaryopoiesis

Dx: diagnosis
Pr: prognosis
Tx: treatment

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