HEMATOLOGY LECTURE

TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

QUALITATIVE PLATELET DISORDERS  If the GP Iib/IIIa did not form a complex (a iiib & B3) it will
 Acquired or Congenital disorder of platelet function - not be expressed by the PLT.
Excessive bruising and superficial (mucocutaneous)
bleeding in a patient whose platelet count is normal  B3 MUTATION
 1960s - began rapid progress in underlying these → Component of vitronectin receptor
disorders, following the development of instruments → Vitronectin - plays a role in vascularization
and test methods for measuring platelet function. → Unclear pathophysiology

DISORDERS OF PLATELET AGGREGATION (GPIIb/IIIa)

C. Classification:
 Type 1 - 0-5% of Normal GP IIb/IIIa
I. GLANZMANN THROMBASTHENIA (GT)
 Type 2 - 10-20% of Normal; Have more GP IIb/IIIa
 Bleeding disorder associated with abnormal in vitro
(Less affected by abnormal clot retraction and
clot retraction and a normal platelet count.
fibrinogen binding)
 Clot retraction - process by which the volume of a
formed clot is reduced through contraction of the
intracellular actin-myosin cytoskeleton of activated D. Laboratory Features:
platelets incorporated in the clot. → Normal Platelet Count
 Inherited as an autosomal recessive disorder and is → Normal Platelet Morphology
seen most frequently in populations with a high degree → Abnormal bleeding time
of consanguinity. → Abnormal Clot Retraction
 Heterozygotes/Heterozygous - 50% to 60% normal → ECA (Epinephrine, Collagen, ADP) - Abnormal
 Homozygotes/Homozygous - serious bleeding → Normal Ristocetin
problems (Lack surface-expressed GP IIb/IIIa) → Lack of platelet aggregation in response to all
platelet activating agents (adenosine diphosphate
A. Manifestation: ADP, collagen, thrombin, and epinephrine)
 Prolonged bleeding which decreases with age → Ristocetin-induced binding of VWF to platelets and
the resulting platelet agglutination are NORMAL.
 Manifest itself clinically in the neonatal period or
infancy (bleeding after circumcision and with epistaxis → Tests for platelet procoagulant activity, such as the
and gingival bleeding) platelet factor 3 test, usually show diminished
activity, for several reasons.
 Hemorrhagic manifestations include petechiae,
purpura, menorrhagia, gastrointestinal bleeding, and
hematuria. E. Signs and Symptoms:
 The severity of the bleeding episodes seems to  Thrombasthenia is one of the few forms of platelet
decrease with age. dysfunction in which hemorrhage is severe and disabling.
Bleeding of all types, including epistaxis, ecchymosis,
hemarthrosis, subcutaneous hematoma, menorrhagia, and
B. Pathophysiology
gastrointestinal and urinary tract hemorrhage
→ deficiency or abnormality of the platelet
membrane glycoprotein (GP) IIb/IIIa (integrin
F. Treatment:
aIIbb3) complex
→ Membrane receptor capable of binding  Platelet Transfusion - for bleeding symptoms
fibrinogen  Affected platelets may interfere with transfused platelets →
→ Von Willebrand Factor (VWF) Increase amount of transfusion
→ Fibronectin  Alloimmunization
→ Other adhesives ligands  Hormonal therapy (norothindrone acetate - menorrhagia)
 Binding of fibrinogen to the GP IIb/IIIa complex  Antifibrinolytic therapy (aminocaproic acid, tranexamic acid
mediates normal platelet aggregation responses. - gingival hemmorrhage/excessive bleeding in tooth
 Failure of such binding results in a profound defect in extraction)
hemostatic plug formation and the serious bleeding  Recombinant factor VIIa (rVIIa; Novoseven, Novo) - surgical
characteristic of thrombasthenia and nonsurgical bleeding in patients with GT
 Genetic mutations are distributed widely over the
ITGA2B and ITGB3 genes present on chromosome 17, DISORDERS OF PLATELET ADHESION (GP Ib/IX/V FUNCTION)
which code for GP IIb/IIIa.
 GP IIb (αIIb) = megakaryocytes (pro-αIIb) I. BERNARD-SOULIER (GIANT PLATELET SYNDROME)
 GP IIIa (β3) = endoplasmic reticulum  Aka Hemorrhagiparous thrombocytic dystrophy
 Transported to the Golgi apparatus, cleaved to heavy  Inherited autosomal recessive disorder
and light chains to form the complete complex.  Rare disorder of platelet adhesion
 Uncomplexed aIIb and b3 are not processed in the Golgi  Manifest in infancy or childhood with hemorrhage
body. characteristics of defective platelet function: ecchymoses,
 Proteins of the GP IIb/IIIa complex must be produced epistaxis, and gingival bleeding.
and assembled into a complex in order to be expressed  Hemarthroses and expanding hematomas are rarely seen.
on the platelet surface.
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 GP Ib/IX/V complex is missing from the platelet  BSS platelets have normal aggregation responses to ADP,
surface or exhibits abnormal function. epinephrine, collagen, and arachidonic acid.
 Inability to bind to VWF accounts for the inability of  Do not respond to ristocetin (lack of response is due to the
platelets to adhere to exposed subendothelium and lack of GP Ib/IX/V complexed and the inability of BSS
the resultant bleeding characteristic of this disorder. platelets to bind VWF)
 Resembled defects seen in von Willebrand disease,  Have dimished response to thrombin
but this disorder abnormality cannot be corrected by
the addition of normal plasma or cryoprecipitate. D. Treatment
 Heterozygotes - 50% of normal levels of GP Ib, GP V,  Antifibrinolytic therapy (mucosal bleeding)
and GP IX have normal or near-normal platelet  There is no specific treatment for more severe bleeding
function. associated with BSS.
 Homozygotes - enlarged platelets, thrombocytopenia,  Platelet Transfusions (therapy of choice) but patients
and usually decreased platelet survival → moderate to invariably develop alloantibodies, limiting further platelet
severe bleeding disorder transfusions.
 Desmopressin acetate (DDAVP)
A. Pathophysiology  Recombinant factor VIIa
 Four glycoproteins are required to form the GP Ib/IX/V  BSS patients tend to do better when apheresis platelets are
complex: GP Ibα, GP Ibβ, GP IX, and GP V. used for transfusion.
 These proteins are present in the ratio of 2:2:2:1  Platelets used to treat BSS should be pre-storage
 Surface expression of the GP Ib/IX complex - leukoreduced to (to reduce alloimmunization)
synthesis of GP Ibα, GP Ibβ, and GP IX is required.  Antiplatelet therapy SHOULD BE AVOIDED
 The most frequent forms of BSS involve defects in GP
Ibα synthesis or expression. II. INHERITED GIANT PLATELET SYNDROMES
 GP Ibα is essential to normal function because it  Exhibit large platelets and thrombocytopenia
contains binding sites for VWF and thrombin.  Thrombocytopenia tends to be mild and bleeding tendency,
 Defects in the GP Ibβ and GP IX genes also are known if present is also mild.
to result in BSS.  Platelet ultrastructure is generally normal.
 Missense, frameshift, and nonsense mutation have all  Platelets used to treat BSS should be pre-storage
been reported.
leukoreduced to (to reduce alloimmunization)

B. Variants GIANT PLATELETS WITH VELOCARDIOFACIAL SYNDROME

 Several unusual variants of BSS have been described in  Autosomal recessive
which the surface expression of the GP Ib/IX/V
 Platelet count: 100-200 x 109/L
complex is normal, but its functionality is impaired.
 Bleeding: NONE REPORTED
 Mutations that affect binding domains - impair
interactions between elements of the complex, or they  Velopharyngeal insufficiency, conotruncal heart disease
result in truncation of a specific protein in the complex,  Mild thrombocytopenia
resulting in complexes that fail to bind VWF or ddo so  Giant platelets
poorly.  GPIβ mapped on chromosome 22q11.2,14
 Antibody to GP Ib/V - cause a Bernard-Soulier-like
syndrome (pseudo-BSS) in which the GP Ib/IX/V GIANT PLATELEETS WITH ABNORMAL SURFACE GLYCOPROTEINS
complex is nonfunctional. AND MITRAL VALVE INSUFFICIENCY
 Gain-of-function mutation in the GP Ib/IX/V complex -  Autosomal recessive
result in platelet-type VWD (pseudo-VWD).
 Platelet count: 50-60 x 109/L
 Such mutations result in spontaneous binding of
 Mild Bleeding (Ecchymoses, epistaxis)
plasma VWF to the mutated GP Ib/IX/V complex.
 Mitral valve insufficiency
 As a consequence, platelets and large VWF multimers
with their associated factor VIII are removed from the  Giant platelets (20μm)
circulation, resulting in thrombocytopenia and  Absent platelet surface glycoproteins: GP Ia, GP Ic, GP IIa
reduced factor VIII clotting activity.  Normal: GP Ib, GP IIb, and GP IIIa

C. Laboratory Features
FAMILIAL MACROTHROMBOCYTOPENIA WITH GP IV
→ Platelet counts - 40,000/μL to near normal ABNORMALITY
→ Platelets - 5 to 8 μm in diameter (peripheral  Autosomal dominant
blood films)
 45 x 109/L to normal
→ Normal platelets - 2 to 3 μm in diameter, but
 Mild bleeding
they can be as large as 20 μm.
 Defective GP IV glycosylation
→ Viewed by Electron Microscopy (platelets
contain larger number of cytoplasmic vacoules  Normal GP IV levels
and membrane complexes, and  Early stages of adhesion (mild bleeding tendencies)
megakaryocytes exhibit an irregular
demarcation membrane system.
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 Thrombocytopenia, Giant platelets, variable degree of

bleeding disorder)
MONTREAL PLATELET SYNDROME DISORDERS OF PLATELET SECRETION
 Autosomal dominant  Storage pool and release reaction defects are the most
 5-40 x 109/L common of the hereditary platelet function defects.
 Significant bruising  Mucotaneous hemorrhage, hemayuria, epistaxis,
 Low calpain activity; defective regulation of binding spontaneous bruising
sites for adhesive proteins  Exacerbated by aspirin/antiplatlet agents.
 Severe thrombocytopenia, giant platelets  In most of these disorders the platelet count is normal
 Spontaneous platelet aggregation  Platelet aggregation abnormalities are usually seen, but
 Large platelets with normal structure vary depending on the disorder.

MAY-HEGGLIN ANOMALY STORAGE POOL DISEASES

 Autosomal dominant  Related to defects of the dense granules or defects of α-
 60-100 x 109/L (thrombocytopenia) granules.
 Mild bleeding
Platelet Storage Pool Diseases
 Dohle body-like neutrophil inclusions
Dense Granule Deficiencies
FLETCHER SYNDROME Hermansky-Pudlak syndrome
 Autosomal dominant Chediak-Higashi syndrome
 30-90 x 109/L Wiskott-Aldrich syndrome
 Deafness, cataracts, nephritis Thrombocytopenia-absent radius (TAR) syndrome
α-Granule Deficiencies
SEBASTIAN SYNDROME Gray platelet syndrome
 Rare autosomal dominant
 40-120 x 109/L I. DENSE GRANULE DEFICIENCY
 Mild bleeding (epistaxis, possible postoperative  The dense granules are the storage site for serotonin,
hemorrhage nucleotides (e.g, ADP and ATP), calcium, and pyrophosphate.
 Neutrophil inclusions, giant platelets  Can be subdivided into deficiency states associated with
albinism and those normal individuals (nonalbinos).
 EM: Normal platelet ultrastructure
 Non-albinos - presence of dense granule membrane in
normal to near normal numbers (disorder arises from
HEREDITARY MACROTHROMBOCYTOPENIA
inability to package the dense granules contents.)
 Autosomal dominant  Serotonin - accumulates in normal dense granules by an
 50-120 x 109/L (mild thrombocytopenia) active uptake mechanism. (It also transport mechanisms a
 Mild bleeding (gingival bleeding, epistaxis, easy nucleotide transporter, MRP4 (ABCC4).
bruising, menorrhagia)  MRP4 (ABCC4) highly expressed in platelets and dense
 High-frequency hearing loss granules has been identified.
 Giant platelets, presence of glycophorin A on platelet  Bleeding is usually mild and most often is limited to easy
surface bruising.
 The impact of dense granule deficiency can be observed in
EPSTEIN SYNDROME platelet aggregation tests.
 Rare autosomal dominant  The contents of these granules are extruded when platelet
 30-60 x 109/L secretion is induced, and secreted ADP plays a major role in
 Mild bleeding (Epistaxis, GI bleeding, female genital platelet activation, recruitment, and aggregation and growth
tract) of the hemostatic plug.
 Platelet function tests:
 Nephritis, high-frequency hearing loss, proteinuria
→ Arachidonic acid to platelet-rich plasma fails to
 Giant spherical platelets with prominent surface
induce an aggregation response from platelets with
connected canalicular system
dense granule deficiency
 Mild bleeding diathesis
→ Epinephrine and low-dose ADP induce a primary
 Large platelets wave of aggregation, but a secondary wave is missing.
→ Low concentrations of collagen are decreased to
MEDITERRANEAN MACROTHROMBOCYTOPENIA absent.
 89-290 x 109/L (thrombocytopenia) → High concentration of collagen may induce a near-
 Stomatocytes in peripheral blood normal aggregation response.

Epinephri ADP Arachidoni Low High

ne (low) c Acid Collagen Collagen
WEAK WEAK (-) WEAK (+)
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 This aggregation pattern, which is nearly identical to and ever-increasing susceptibility to infection → Death at
the pattern observed in patients taking aspirin, is an early age.
caused by the lack of ADP secretion.  Initially bleeding is increased because of dense granule
deficiency and consequent defective platelet function
1. HERMANSKY-PUDLAK SYNDROME  During the accelerated phase, however, the
 Autosomal recessive disorder thrombocytopenia also contributes to a prolonged bleeding
 Characterized by: tendency.
→ tyrosinase-positive oculocutaneous albinism  Bleeding episodes vary from mild to moderate but worsen as
the platelet count decreases.
→ defective lysosomal function in a variety of cell
types
→ ceroid-like deposition in the cells of the 3. WISKOTT-ALDRICH SYNDROME (WAS)
reticuloendothelial system  Rare X-linked disease
→ profound platelet dense granule deficiency.  Caused by mutations in the WAS gene on the short arm of
 Mutation responsible have been mapped to the X Chromosome Xp11.23 that encodes for 502-amino acid
Chromosome 19 protein.
 These genes encode for proteins that are involved in  Wiskott-Aldrich syndrome protein WASp (502-amino acid) -
intracellular vesicular trafficking and are active in the found in hematopoietic cells and lymphocytes. It plays a
biogenesis of organelles. crucial role in actin cytoskeleton remodeling.
→ T cell function is defective due to abnormal
A. Manifestations: cytoskeletal reorganization
→ Impaired migration
 Bleeding episodes are not severe, but lethal
hemorrhage has been reported. → Impaired adhesion
 Abnormality consists of marked dilation and tortuosity → Insufficient interaction with other cells
of the surface-connecting tubular system (the so called  Disease severity associated with WAS gene mutations ranges
Swiss cheese platelet). from the classic form of WAS with autoimmunity and/or
malignancy, to a milder form with isolated
microthrombocytopenia (X-linked thrombocytopenia [XLT]),
B. Treatment:
to X-linked neutropenia (XLN).
 For extensive surgery or prolonged bleeding both red
blood cell (RBC) and platelet transfusions are required.  Approximately 50% of patients with WAS gene mutations
have the WAS phenotype, and the other half have the XLT
 Thrombin-soaked Gelfoam can be used to treat skin phenotype.
wounds that fail to spontaneously clot.
 WAS gene mutations causing XLN are very rare.
 Oral contraceptives can limit the duration of
 Homozygous mutations of the WIPF1 gene on chromosome 2
menstrual periods.
that encodes WASp-interacting protein (WIP) – a
cytoplasmic protein required to stabilize WASp – can also
2. CHEDIAK-HIGASHI SYNDROME cause a WAS phenotype.
 Rare autosomal recessive disorder
 Characterized by: A. Classification:
→ Partial oculocutaneous albinism  Classic form of WAS (eczemathrombocytopenia
→ Frequent pyogemic bacterial infections immunodeficiency syndrome)
→ Giant lysosomal granules in cells of hematologic → characterized by susceptibility to infections
and nonhematologic origin associated with immune dysfunction, with recurrent
→ Platelet dense granule deficiency bacterial, viral, and fungal infections,
→ Hemorrhage microthrombocytopenia, and severe eczema.
 The disorder is accompanied by severe immunologic → Thrombocytopenia is present at birth, but the full
defects and progressive neurologic dysfunction in expression of WAS develops over the first 2 years of
patients who survive to adulthood. life.
 The gene for the Chédiak-Higashi syndrome protein is → Lack the ability to make antipolysaccharide antibodies,
located on Chromosome 1 (1q42.3). which results in a propensity for pneumococcal sepsis.
 A number of nonsense and frameshift mutations result → Develop autoimmune disorders, lymphoma, or other
in a truncated Chédiak-Higashi syndrome protein that malignancies, often leading to early death.
gives rise to a disorder of generalized cellular → Bleeding episodes are typically moderate to severe.
dysfunction involving fusion of cytoplasmic granules.  In WAS a combination of ineffective thrombocytopoiesis and
increased platelet sequestration and destruction accounts for
A. Manifestation: the thrombocytopenia.
 In 85% of patients with Chédiak-Higashi syndrome the  As with all X-linked recessive disorders, it is found primarily in
disorder progresses to an accelerated phase that is males.
marked by lymphocytic proliferation in the liver,
spleen, and marrow with macrophage accumulation B. Laboratory Features:
in tissues → Pancytopenia worsens → hemorrhage  Platelets are also structurally abnormal.
 Dense granules is decreased
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 Platelets are small (microthrombocytes) A. Laboratory Features:

 Such small platelets are seen only in association with  Platelets and megakaryocytes - no α-granules, but contain
TORCH (toxoplasma, other agents, rubella virus, vacoules and small α-granules precursors that stain positive
cytomegalovirus, herpesvirus) infections. for VWF and fibrinogen.
 Diminished levels of stored adenine nucleotides are  Other types of granules - present in normal numbers
reflected in the lack of dense granules observed on
transmission electron micrographs. B. Pathophysiology
 In laboratory testing the platelet aggregation pattern in  Membranes of the vacoules and the α-granules precursor
WAS is typical of a storage pool deficiency. have P-selectin (CD62) and GP IIb/IIIa, which can be
 The platelets show a decreased aggregation response translocated to the cell membrane upon platelet stimulation
to ADP, collagen, and epinephrine and lack a secondary with thrombin.
wave of aggregation in response to these agonists  This suggests that these structures are α-granules that
 The response to thrombin is normal. cannot store the typical α-granules proteins.
 Plasma levels of platelet factor 4 and β-thromboglobulin are
C. Treatment increased, because although the proteins normally contained
 Splenectomy (most effective), which would be in α-granules are produces, storage in those granules is not
consistent with a mechanism of peripheral destruction possible.
of platelets.  As a result the proteins are released into circulation.
 Platelet transfusions may be needed to treat
hemorrhagic episodes. C. Manifestations:
 Bone marrow transplantation also has been  Most patients develop early-onset myelofibrosis, which can
attempted, with some success. be attributed to the inability of megakaryocytes to store
newly synthesized platelet-derived growth factors.
4. THROMBOCYTOPENIA WITH ABSENT RADII SYNDROME
 Rare autosomal recessive disorder D. Treatment:
 Characterized by:  Platelet transfusion (severe bleeding episodes)
→ Congenital absence of the radial bones (the  Cryoprecipitate (control bleeding)
most pronounced skeletal abnormality)  Desmopressin acetate (shorten bleeding time test &
→ Numerous cardiac and other skeletal prophylaxis)
abnormalities
→ Thrombocytopenia 2. ALPHA DENSE STORAGE POOL DEFICIENCY
 Platelets have structural defects in dense granules  Rare disorder in which both α-granules and dense granules
 Abnormal aggregation responses are deficient.
 Marrow megakaryocytes - decreased in number,  Inherited in an autosomal dominant manner
immature, or normal.
3. QUEBEC PLATELET DISORDER
II. ALPHA GRANULE DEFICIENCY (α-granule)  Autosomal dominant bleeding disorder
 Platelet α-granules - storage site for proteins and is  Result from a deficiency of multimerin
produced by megakaryocyte or present in plasma and  Multimerin - a multimeric protein that is stored complexed
taken up by platelets and transported to α-granules with factor V in α-granules.
for storage.
 Even though a-granule structure is maintained, many a-
 E.g. Albumin, immunoglobulin G (IgG), and fibrinogen granule proteins show signs of protease-related degradation.
 There are 50 to 80 α-granules per platelet, which are  Thrombocytopenia may be present, although it is not a
responsible for the granular appearance of platelets on consistent feature.
stained blood films.
THROMBOXANE PATHWAY DISORDERS: ASPIRIN-LIKE EFFECTS
1. GRAY PLATELET SYNDROME  Platelet secretion requires the activation of several
 Rare disorder first described in 1971 biochemical pathways. One such pathway leads to
 Inherited in an autosomal recessive fashion thromboxane formation.
 Mutation in region 3p21.31 involving the gene NBEAL2  A series of phospholipases catalyze the release of arachidonic
- a gene crucial for the development of α-granules. acid and several other compounds from membrane
 Characterized by: phospholipids.
 Specific absence of α-granules in platelets  Arachidonic acid is converted to intermediate prostaglandins
by cyclooxygenase and to thromboxane A2 by thromboxane
 Lifelong mild bleeding tendencies
synthase.
 Moderate thrombocytopenia
 Thromboxane A2 and other substances generated during
 Fibrosis of the marrow
platelet activation cause mobilization of ionic calcium from
 Large platelets (Gray on Wright-stained blood internal stores into the cytoplasm, initiating a cascade of
film) events resulting in secretion and aggregation of platelets.

SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

Arachidonic Acid Pathway Enzymes  P2Y1 and P2Y12 (P2TAC) - members of the seven-
 Several acquired or congenital disorders of platelet transmembrane domain (STD) family of G protein-linked
secretion can be traced to structural and functional receptors.
modifications of arachidonic acid pathway enzymes.  P2Y1 - mediate calcium mobilization and shape change in
response to ADP. Pathology of the P2Y1 receptor has not yet
Inhibition of Cyclooxygenase been reported.
 Occurs following ingestion of drugs such as aspirin and  P2Y12 - responsible for macroscopic platelet aggregation and
ibuprofen. is coupled to adenylate cyclase through a G-inhibitory (Gi)
protein complex.
 As a result, the amount of thromboxane A2 produced
from arachidonic acid depends on the degree of  Patients with an inherited deficiency of the P2Y12 receptor
inhibition. exhibit decreased platelet aggregation in response to ADP
but normal platelet shape change and calcium mobilization.
 Thromboxane A2 is required for storage granule
secretion and maximal platelet aggregation in response  Bleeding problems seem to be relatively mild in these
to epinephrine, ADP, and low concentrations of patients.
collagen.  The only treatment for severe bleeding is platelet
transfusion.
Aspirin-Like defects
 Hereditary absence or abnormalities of the 3. EPINEPHRINE RECEPTOR
components of the thromboxane pathway.  α2-adrenergic (epinephrine) receptor
 Clinical and laboratory manifestations resemble those  Associated with decreased platelet activation and
that follow aspirin ingestion. aggregation in response to epinephrine
 Platelet aggregation responses are similar to those in  PAR receptors defects have been described in one family.
dense granule storage pool disorders.
 Unlike in storage pool disorders, however, 4. CALCIUM MOBILIZATION DEFECTS
ultrastructure and granular contents are normal.  Defects represents a heterogeneous group of disorders in
 Deficiencies of the enzymes cyclooxygenase and which all elements of the thromboxane pathway are normal.
thromboxane synthase are well documented, and  Insufficient calcium is released from the dense tubular
dysfunction or deficiency of thromboxane receptors is system.
known.
 Cytoplasmic concentration of ionic calcium in the cytoplasm
never reaches levels high enough to support secretion.
OTHER INHERITED DISORDERS OF RECEPTORS AND  Results from abnormal G protein subunits and
SIGNALING PATHWAYS phospholipase C isoenzymes.

1. COLLAGEN RECEPTORS 5. SCOTT SYNDROME

 Deficiency in collagen receptor  Very rare autosomal recessive disorder of calcium-induced
→ α2β1 membrane phospholipid scrambling and thrombin
→ GP VI generation on platelets.
 The α2β1 (GP Ia/IIa) integrin is one of the collagen  Normal aggregation but no “flipping” of membrane
receptors in the platelet membrane.  Phospholipid “flip” normally occurs during platelet activation
 A deficiency of this receptor has been reported in a and is essential for the binding of vitamin K-dependent
patient: clotting factors.
 who lacked an aggregation response to  Normal platelet plug formation (adhesion, aggregation,
collagen secretion) but no formation of clotting factor complex.
 whose platelets did not adhere to collagen
 who had a lifelong mild bleeding disorder. 6. STORMORKEN SYNDROME
 A deficiency in another collagen receptor, GP VI, also  Autosomal dominant disorder
has been reported in patients with mild bleeding.  Characterized by:
 The platelets of these patients failed to aggregate in  Mild bleeding tendency due to platelet dysfunction
response to collagen, and adhesion to collagen also  Thrombocytopenia
was impaired.
 Anemia
 A family with gray platelet syndrome and defective  Functional asplenia
collagen adhesion has been described.
 Other constitutive disorders
 Affected members of the family have a severe
 Condition in which platelets are always in an “activated”
deficiency of GP VI.
state and express phosphatidylserine on the outer leaflet of
the membrane without prior activation.
2. ADENOSINE DIPHOSPHATE RECEPTORS (ADP)
 It has been postulated that patients with this syndrome have
 Platelets contain at least three receptors for ADP. a defective aminophospholipid translocase due to one or
 P2X1- linked to an ion channel that facilitates calcium more mutations that result in constitutive activation of the
ion influx. calcium channel, with resultant inhibition of further
activation.
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

ACQUIRED DEFECTS OF PLATELET FUNCTIONS

 The most frequent cause of acquired platelet
dysfunction is drug ingestion.
 Therapeutic drugs have been developed with the
target of inhibiting platelet function.

Antiplatelet Drugs
Target Drugs
COX-1 (irreversible) Aspirin
COX-1 (reversible) Naproxen
Sulfinpyrazone
Ibuprofen (and like drugs)
ADP P2Y12 (irreversible) Clopidogrel
Prasugrel

ADP P2Y12 (reversible Tincagrelor

Cangrelor

Thrombin PAR-1 Vorapazar

GP IIb/IIIa Abciximab
Epitifibatide
Tirofiban

Phosphodiesterase Dipyridamole
Aggrenox

SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

QUANTITATIVE PLATELET DISORDER syndrome thrombocytopenia

 Fanconi anemia Acquired
I. THROMBOCYTOPENIA: DECREASE IN  Wiskott-Aldrich  Viral or bacterial
syndrome infections
CIRCULATING PLATELETS
 Drug induced
 The most common cause of abnormal bleeding
Neonatal
 Platelet count: 150,000 to 450,000/μL (150,000 to
450,000/mm3 or 150 to 450 X 109/L)
CONGENITAL TYPES OF IMPAIRED PLATELET PRODUCTION
 Thrombocytopenia (platelet count of fewer than
100,000/μL) is the most common cause of clinically  It is increasingly apparent that most inherited
important bleeding. thrombocytopenias can be linked to fairly specific
 True thrombocytopenia has to be differentiated from chromosomal abnormalities or specific genetic defects.
the thrombocytopenia artifact that can result from  Lack of adequate bone marrow megakaryocytes
poorly prepared blood films or automated cell counts (megakaryocytic hypoplasia) is seen in a wide variety of
when platelet clumping or platelet satellitosis is congenital disorders, including:
present.  Fanconi anemia (pancytopenia),
 Small-vessel bleeding in the skin attributed to  Thrombocytopenia with absent radius (TAR)
thrombocytopenia manifests as hemorrhages of syndrome
different sizes.  May-Hegglin anomaly, Wiskott-Aldrich syndrome
→ Petechiae - small pinpoint hemorrhages about  Bernard-Soulier syndrome
1 mm in diameter.  Other less common disorders.
→ Purpura - 3 mm in diameter and generally  Although, thrombocytopenia is a feature of Bernard-Soulier
round syndrome and Wiskott-Aldrich syndrome, the primary
→ Ecchymoses - 1 cm or larger and usually abnormality in these disorders is a qualitative defect.
irregular in shape; corresponds with the lay
term bruise. 1. MAY-HEGGLIN ANOMALY
 Rare Autosomal Dominant Disorder whose exact frequency is
unknown.
 Characterized by:
 Large platelets (20 μm in diameter) present on
peripheral blood film
 Dohle-like bodies are present in neutrophils and
occasionally in monocytes
 Other conditions such as defective platelet function,  Abnormally enlarged or misshapen platelets
vascular fragility, and trauma contribute to the  Platelet function in response to platelet-activating
hemorrhagic state. agents is usually NORMAL
 Possible Causes:  In some patients the number of megakaryocytes is
 Decreased Platelet Production increased and their ultrastructure is ABNORMAL
 Increased Platelet Destruction  Mutations in the MYH9 gene that encodes for nonmuscle
 Increased Platelet Sequestration by Spleen myosin heavy chain (a cytoskeletal protein in platelets) →
 Abnormal Dilution of Platelet Count responsible for the abnormal size of platelets.
 Most patients are asymptomatic unless severe
thrombocytopenia is present.
DECREASED PLATELET PRODUCTION  In severe cases with clinical bleeding, transfusion with
platelets may be necessary.
 Abnormalities in platelet production can result from:
 Megakaryocyte hypoplasia in the bone marrow  Three other disorders involving mutations of the MYH9 gene:
→ Sebastian syndrome - Autosomal dominant
 Ineffective thrombopoiesis.
characterized by large platelets, thrombocytopenia,
 Factors causing decreased platelet production can be
and granulocytic inclusions (Deafness, cataracts, and
congenital or acquired.
nephritis)
→ Fechtner syndrome - Deafness, cataracts, and
Classification of Thrombocytopenias: Impaired or Decreased nephritis
Production of Platelets → Epstein syndrome - Large platelets are associated
Congenital  Thrombocytopenia with deafness, ocular problems, and glomerular
 May-Hegglin anomaly with absent radius nephritis
 Bernard-Soulier (TAR) syndrome
syndrome  Congenital 2. THROMBOCYTOPENIA WITH ABSENT RADIUS (TAR) SYNDROME
 Fechtner syndrome amegakaryocytic  Rare Autosomal Recessive Disorder
thrombocytopenia
 Sebastian syndrome  Characterized by:
 Autosomal dominant
 Epstein syndrome  Severe neonatal thrombocytopenia
and X-linked
 Montreal platelet
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 Congenital absence or extreme hypoplasia of 6. X-LINKED THROMBOCYTOPENIA

the radial bones of the forearms with absent,  Result from mutations in the WAS (Wiskott-Aldrich
short, or malformed ulnae syndrome) gene on the X chromosome (Xp11.23) or
 Other orthopedic abnormalities mutations in the GATA1 gene, also on the X chromosome at
 Platelet counts: 10,000 to 30,000/μL during the Xp11.
first 2 years of infancy  Range from mild thrombocytopenia with small platelets and
 Interestingly, platelet counts usually increase over time, absent or mild bleeding to large platelets with severe
with normal levels usually achieved by the time these bleeding.
children reach school age.
 Associated with a mutation in the RBM8A gene located NEONATAL THROMBOCYTOPENIA
on the long arm of chromosome 1 or a 200 kb deletion  Platelet count: <150,000/μL (present in 1% to 5% of infants
involving the RBM8A gene (1q21.1). at birth).
 In addition to bone abnormalities, up to 90% of  In 75% of cases the thrombocytopenia is present at or within
patients may have cardiac lesions or transient 72 hours of birth.
leukemoid reactions with elevated white blood cell  Such infections cause thrombocytopenia with
(WBC) counts (sometimes with counts .100,000/μL). characteristically small platelets.
 Common causes:
3. FANCONI ANEMIA
→ TORCH (Toxoplasmosis, Other [Treponema pallidum,
 Associated with thrombocytopenia and other varicella-zoster virus, parvovirus B19] Rubella,
abnormalities, including bony abnormalities, Cytomegalovirus, Herpes) syndrome
abnormalities of visceral organs, and pancytopenia. → Impaired platelet production (most common cause)
→ Other causes of neonatal thrombocytopenia include
4. CONGENITAL AMEGARYICYTIC THROMBOCYTOPENIA thrombosis, platelet activation, platelet binding at
 Autosomal Recessive Disorder reflecting bone marrow inflammatory sites such as in necrotizing enterocolitis
failure. and splenic sequestration.
 Characterized by (Affected Infants): → Inherited thrombocytopenic syndromes are
 ≦ 20,000/μL at birth increasingly being recognized as causes of neonatal
 Petechiae thrombocytopenia.
 Evidence of bleeding at or shortly after birth  CMV - most common infectious agent causing congenital
thrombocytopenia.
 Frequent anomalies.
 CMV inhibits megakaryocytes and their precursors, which
 About half of the infants develop aplastic anemia in
result in impaired platelet production.
the first year of life, and there are reports of
myelodysplasia and leukemia later in childhood.  Although infectious agents and certain drugs are well-known
 Allogeneic stem cell transplantation - considered causes of neonatal thrombocytopenia, the most common
cause is impaired platelet production
curative for infants with clinically severe disease or
aplasia.
 Caused by mutations in the MPL gene on chromosome Laboratory Features:
1 (1p34.1), resulting in complete loss of  Maternal ingestion of chlorothiazide diuretics or
thrombopoietin receptor function. tolbutamide oral hypoglycemic medication (both
 Thrombopoietin receptor function - loss of this sulfonamides) can have a direct cytotoxic effect on the fetal
function results in reduced megakaryocyte progenitors marrow megakaryocytes.
and high thrombopoietin levels.  Thrombocytopenia may be severe, with platelet counts of
70,000/mL and sometimes lower.
5. AUTOSOMAL DOMINANT THROMBOCYTOPENIA  Bone marrow examination reveals a marked decrease or
absence of megakaryocytes.
 Mutations in the ANKRD26 gene on the short arm of
chromosome 10 (10p12.1).  Thrombocytopenia develops gradually and is slow to regress
when the drug is stopped.
 Mutations in this gene lead to incomplete
megakaryocyte differentiation and resultant  Recovery usually occurs within a few weeks after birth.
thrombocytopenia.
 ANKRD26 mutations have recently been found in 21 of Manifestations:
210 thrombocytopenic pedigrees, suggesting that  Most patients are preterm neonates born after pregnancies
ANKRD26 mutations may be a relatively common complicated by placental insufficiency or fetal hypoxia
cause of autosomal dominant thrombocytopenia. (preeclampsia and intrauterine growth restriction).
 Characterized by:  These neonates have early-onset thrombocytopenia and
 Bleeding in these patients is usually absent or impaired megakaryopoiesis in spite of increased levels of
mild, and platelet function is usually normal. thrombopoietin
 Platelet morphology and size are usually
normal.

SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

ACQUIRED TYPES OF IMPAIRED PLATELET PRODUCTION  grossly abnormal megakaryocytes

 deformed dumbbell-shaped nuclei (in large numbers)
1. DRUG-INDUCED HYPOPLASIA  Stained peripheral blood films reveal large platelets that may
 Drug-induced hypoplasia of the bone marrow results in have a decreased survival time and may have abnormal
thrombocytopenia. function.
 Chemotherapeutic agents (hematologic and  Thrombocytopenia is usually mild, and there is evidence of
nonhematologic) malignancies - suppress bone increased platelet destruction.
marrow megakaryocytes production and other  Patients typically respond within 1 to 2 weeks to vitamin
hematopoietic cells. replacement
→ E.g. methotrexate, busulfan, cytosine
arabinoside, cyclophosphamide, and cisplatin 2. VIRAL OR BACTERIAL INFECTIONS
 Drug-induced thrombocytopenia is often the dose- Infectious Conditions
limiting factor for many chemotherapeutic agents.  Infectious conditions, such as with viruses, are known to
cause thrombocytopenia by acting on megakaryocytes or
Long-term ingestion of ethanol (months to years) circulating platelets, either directly or in the form of viral
 May result in persistent, severe thrombocytopenia. antigen-antibody complexes.
 Alcohol can inhibit megakaryocytopoiesis.  Live measles vaccine - cause degenerative vacuolization of
 Mild thrombocytopenia - common in alcoholic megakaryocytes 6 to 8 days after vaccination.
patients and also,  Other virus associated with thrombocytopenia include:
 Portal hypertension  CMV
 Splenomegaly  Varicella-zoster cirus
 Folic acid deficiency can also contribute  Rubella virus
 The platelet count usually returns to normal within a  Epstein-Barr (infectious mononucleosis)
few weeks of alcohol withdrawal, but  Serotypes of dengue virus that cause Thai
thrombocytopenia may persist for longer periods. hemorrhagic fever
 A transient rebound thrombocytosis may develop  Certain bacterial infections are commonly associated with
when alcohol ingestion is stopped. the development of thrombocytopenia and may be result of:
 Toxins of bacterial origin
Interferon therapy  Direct interactions between bacteria and platelets in
 Commonly causes mild to moderate thrombocytopenia the circulation
but under certain circumstances it can be severe and  Extensive damage to the endothelium, as in
life threatening. meningococcemia.
 Interferon-α and Interferon-γ - inhibit stem cell  Many cases of thrombocytopenia in childhood result from
differentiation and proliferation in the bone marrow. bacterial infection

Megakaryocyte Suppression Infiltration of the Bone Marrow

 Administration of large doses of estrogen or estrogenic  Infiltration of the bone marrow by malignant cells can cause
drugs such as diethylstilbestrol. thrombocytopenia.
 Certain antibacterial agents (e.g., chloramphenicol),  Results to progressive decrease in marrow megakaryocytes
tranquilizers, and anticonvulsants also have been as the abnormal cells replace normal marrow elements.
associated with thrombocytopenia caused by bone  Inhibitors of thrombopoiesis may be produced by these
marrow suppression. abnormal cells and may contribute to the thrombocytopenia
associated with conditions such as myeloma, lymphoma,
Ineffective Thrombosis metastatic cancer, and myelofibrosis.
 Ineffective thrombosis can also occur.
 Thrombocytopenia is a usual feature of the INCREASED PLATELET DESTRUCTION
megaloblastic anemias:  Two categories:
 pernicious anemia a. Immunologic Responses
 folic acid deficiency b. Mechanical damage, consumption, or sequestration
 vitamin B12 deficiency  Increased production is required to maintain a normal
platelet count, and thrombocytopenia develops only when
Laboratory Features: production capacity is no longer adequate to compensate for
 Erythrocyte production in these disorders, platelet the increased rate of destruction.
production is ineffective.
 Although the bone marrow generally contains an IMMUNE MECHANISMS OF PLATELET DESTRUCTION
increased number of megakaryocytes, the total
number of platelets released into the circulation is 1. IMMUNE THROMBOCYTOPENIC PURPURA
decreased.  Idiopathic thrombocytopenic purpura (ITP) was used
 Thrombocytopenia is caused by impaired DNA previously to describe cases of thrombocytopenia arising
synthesis, and the bone marrow may contain: without apparent cause or underlying disease state.
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 The word idiopathic has been replaced by immune A. Acute ITP

after the realization that acute and chronic ITP are  Disorder of children (often in children 2 to 9 years of age)
immunologically mediated.  Characterized by:
 Abrupt onset of bruising
Manifestation:  Petechiae
 Life span of the platelet is shortened from the normal 7  Mucosal bleeding (epistaxis)
to 10 days to a few hours.
 Ecchymoses
 The rapidity with which platelets are removed from the  Hematuria
circulation correlates with the degree of
 The primary hematologic feature is thrombocytopenia, which
thrombocytopenia.
often occurs 1 to 3 weeks after an infection.
 If plasma from a patient with ITP is transfused into the
 Self-limited, and spontaneous remissions occur in 80% to
circulation of a normal recipient, the recipient
90% of patient
develops thrombocytopenia.
 The thrombocytopenia producing factor in the plasma  Duration of the ilness may range from days to months
of the ITP patient is an immunoglobulin G (IgG)  Symptoms:
antibody that can be removed from serum by → Petechial hemorrhages
adsorption with normal human platelets. → Purpura
→ Bleeding from the gums
Laboratory Features: → Gastrointestinal or urinary tract bleeding
 Platelets number between 30,000/μL and 80,000/μL. → Hemorrhagic bullae in the oral mucosa are often
 Platelets appear normal, although larger in diameter prominent in patients with severe thrombocytopenia
than usual.  Diagnosis:
 This is reflected in an increased mean platelet volume → Can be made without a bone marrow examination
as measured by electronic cell counters. → Onset of bleeding signs
 Patients with ITP undergo periods of remission and → Normal results on CBC (RBC, WBC, morphology)
exacerbation, however, and their platelet counts may → Normal findings on physical examination (except signs
range from near normal to fewer than 20,000/μL of bleeding)
during these periods.  There is, at present, no specific test that is diagnostic of
 The marrow typically is characterized by acute or chronic ITP.
megakaryocytic hyperplasia.  Considered severe, with platelet counts ,10,000/mL and
 Megakaryocytes are increased in size, and young forms noncutaneous bleeding such as gastrointestinal bleeding,
with a single nucleus, smooth contour, and diminished hematuria, mucous membrane bleeding, and retinal
cytoplasm are common. hemorrhage.
 Coagulation tests showing abnormal results include  Most patients with acute ITP recover with or without
tests dependent on platelet function. treatment in about 3 weeks, although for some, recovery
 Although platelet-associated IgG levels are increased in may take 6 months.
most patients, such testing for IgG platelet antibodies  If thrombocytopenia persists for 6 months or longer, and
is neither sensitive or specific for ITP and therefore is these children are reclassified as having chronic ITP.
not diagnostically useful for any form of ITP
 Treatments:
Differentiation of Acute and Chronic Immune Thrombocytopenic → Corticosteroids
Purpura (ITP) → Intravenous immunoglobulin (IVIG)
Characteristic Acute ITP Chronic ITP → Anti-D immunoglobulin is provided to treat
Age at onset 2-6 yr 20-50 yr hemorrhage.
Sex predilection None Female over male, → Splenectomy is rarely required
3:1
Prior infection Common Unusual
Gradual
B. Chronic ITP
Onset of bleeding Sudden
Platelet count <20,000/μL 30,000-80,000/μL  Can be found in patients of any age
Duration 2-6 weeks Months to years  Most cases occur in patients between the ages of 20 and 50
Spontaneous remission 90% of patients Uncommon years
 Highest incidence in women between 20 and 40 years of age.
Seasonal pattern Higher incidence None (2 to 3:1)
in winter and
spring  Chronic ITP usually begins insidiously, with platelet counts
that are variably decreased and sometimes normal for
Therapy:
70% response 30% response rate
periods.
Steroids
rate  There is typically a fluctuating clinical course, with episodes
Splenectomy
Rarely required <45yr, 90% of bleeding that last a few days or weeks.
response rate  Spontaneous remissions are uncommon and usually
>45 yr, 40% incomplete.
response rate
 Symptoms:
 Mucocutaneous bleeding

SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 Menorrhagia  Laboratory Features:

 Recurrent epistaxis  Initial platelet count of <10,000/μL and sometimes
 Easy bruising (ecchymoses) being most <1000/μL
common.  Number of bone marrow megakaryocytes is usually
 Scattered petechiae normal to elevated
 Minor bleeding  Bleeding is often severe and rapid is onset
 Platelet counts: 5000/μL to 75,000/μL  Hemorrhagic bullae in the mouth
 Giant platelets are common C. Drug-induced autoantibodies
 Platelet destruction is the result of the binding of  Represent a third mechanism of drug-induced
autoantibodies to platelets, which leads to enhanced thrombocytopenia.
platelet removal from the circulation by  Drugs stimulate the formation of an autoantibody that binds
reticuloendothelial cells, primarily in the spleen. to a specific platelet membrane glycoprotein with no
 Treatment: requirement for the presence of free drug.
→ Initial theraphy often consists of glucocorticoids  Examples of drugs:
(corticosteroids), which interfere with splenic  Gold salts
and hepatic macrophages to increase platelet  Procainamide
survival time.  Levodopa
 The precise mechanism by which these drugs induce
2. IMMUNOLOGIC DRUG-INDUCED THROMBOCYTOPENIA autoantibodies against platelets is not known with certainty.
 Drug-dependent antibodies typically occur after 1 to 2
weeks of exposure to a new drug. D. Immune complex-induced thrombocytopenia
 Drug-induced immune-mediayed thrombocytopenia  Heparin-induced thrombocytopenia (HIT) is a good example.
can be divided into several types based on the
 The fourth mechanism of drug-induced thrombocytopenia.
mechanisims underlying the interaction of the
antibody with the drug and platelets.  Binding of therapeutic heparin to platelet factor 4 (PF4), a
protein released by activated platelets, or binding of PF4 to
the platelet membrane causes a conformational change in
A. Drug-dependent antibodies
PF4, resulting in the exposure of neoepitopes.
 One mechanism of drug-dependent antibodies for
 The Fab portion of an IgG binds to the PF4 neoepitope.
more than 100 years is typified by quinidine- and
quinine-induced thrombocytopenia.  The free Fc portion of the IgG binds with the platelet FcgIIa
receptor. Platelets are activated by occupancy of their FcgIIa
→ Antibodies induced by drugs of this type
receptor, leading to platelet activation and aggregation.
interact with platelets only in the presence of
the drug.  It is this activation of platelets that leads to their
consumption and thrombocytopenia.
 Many drugs can induce such antibodies, but quinine,
quinidine, and sulfonamide derivatives do so more  Thrombocytopenia, typically beginning 5 to 14 days after
often than other drugs. heparin exposure, is usually mild to moderate.
 Symptoms:  Symptoms:
 Abrupt onset bleeding symptoms  Platelet counts only rarely <15,000/μL
 Platelet count falls rapidly and often may be  Patients rarely bleed
<10,000/μL (antibody production begun)  High risk of thrombosis (can be life threatening)
 If this type of drug-induced thrombocytopenia
develops in a pregnant woman, both she and her 3. NEONATAL IMMUNE-MEDIATED THROMBOCYTOPENIAS
fetus may be affected. A. Neonatal alloimmune thrombocytopenia (NAIT)
 The antibodies responsible for drug-dependent  Develops when the mother lacks a platelet-specific antigen
thrombocytopenia bind directly to platelets by their that the fetus has inherited from the father.
Fab regions.  Fetal platelet antigens - are inherited as codominant genes,
 Fab portion of the antibody binds to a platelet may pass from the fetal to the maternal circulation as early
membrane constituent, usually the GPIb/IX/V complex as the 14th week of gestation.
or the GPIIb/IIIa complex, only in the presence of drug  These IgG antibodies cross the placenta, attach to the
 IgG class - most drug-induced platelet antibodies (IgM antigen-bearing fetal platelets, and result in
rare instances) thrombocytopenia in the fetus
 Characterized by:
B. Hapten-induced antibodies  Asymptomatic
 A second mechanism of drug-induced  Similar to that of hemolytic disease of the newborn
thrombocytopenia is induction of hapten-dependent (HDFN)
antibodies.  Common cause (80%) Caucasians is the HPA-1a
 Penicillin and penicillin derivatives are the primary antigen expressed on GPIIIa of the surface membrane
offending agents causing drug-induced GPIIb/IIIa complex
thrombocytopenia by this mechanism.  HPA-5b (Br) - is found on the GPIa, accounts for 10% to 15%
 Drug-induced thrombocytopenia of this type is often of cases
severe.
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 Antigen HPA-3a (Bak) - present on GPIIb and is an  No clinical trials

important cause of neonatal thrombocytopenia in  Therapeutic exchange transfusion
Asians.  IVIG (treatment of choice)
 Antigen HPA-4 (Pen, Yuk) accounts for the disorder in  Corticosteroid therapy is not particularly efficacious when
a few affected neonates used alone but may be beneficial in combination with other,
 Clinically severe thrombocytopenia as a result of NAIT more effective treatments.
occurs in 1 in 1000 live births and, unlike hemolytic
disease of the fetus and newborn, often affects the 5. SECONDARY THROMBOCYTOPENIA, PRESUMED TO BE IMMUNE
first pregnancy in an at-risk couple. MEDIATED
 Symptoms:  Severe thrombocytopenia has been identified in patients
 Affected infants may appear normal at birth receiving biologic response modifiers such as interferons,
 Scattered petechiae colony-stimulating factors, and interleukin-2.
 Purpuric hemorrhages  Immune thrombocytopenia develops in about 5% to 10% of
 Platelets levels are usually <30,000/μL and may patients with chronic lymphocytic leukemia and in a smaller
decrease even further in the first few hours percentage of patients with other lymphoproliferative
after birth disorders.
 Diagnosis:  Parasitic infections also are known to cause
 Presence of thrombocytopenia in a neonate thrombocytopenia.
with a HPA-1a-negative mother  Malaria is the most studied disease in this group and is
 History of the disorder in a sibling regularly accompanied by thrombocytopenia.
 Platelet typing of both parents and Maternal  Immune destruction of platelets seems to be the most likely
antibody directed at paternal platelets (for mechanism for the thrombocytopenia.
confirmation)  Most patients with PTP are multiparous middle-aged women
and almost all patients have a history of blood transfusion.
B. Neonatal autoimmune thrombocytopenia
 Results from the passive transplacental transfer of NONIMMUNE MECHANISMS OF PLATELET DESTRUCTION
maternal ITP autoantibodies or, less commonly, from  Nonimmune platelet destruction may result from
autoantibodies associated with a collagenvascular  exposure of platelets to nonendothelial surfaces
disease such as systemic lupus erythematosus.  activation of the coagulation process
 The neonate does not have an ongoing autoimmune  platelet consumption by endovascular injury without
process per se, but rather is an incidental target of the measurable depletion of coagulation factors.
mother’s autoimmune process.
 Disorders are classified as thrombotic microangiopathies
 Symptoms: (TMAs) broad group of disorders characterized by the
 Normal to decreased platelet numbers at birth presence of thrombocytopenia, clot formation within the
 Progressive decrease in platelet count for about arterioles and capillaries, and microangiopathic hemolytic
1 week postpartum (could last for months) anemia.
 Treatment:
 Corticosteroids are the primary treatment for 1. THROMBOCYTOPENIA IN PREGNANCY AND PREECLAMPSIA
pregnant women with ITP, and at the dosages
used, there is a low incidence of adverse fetal A. Pregnancy-Associated Thrombocytopenia & Gestational
side effects Thrombocytopenia
 IVIG treatment, platelet transfusion (if develops  Benign physiologic condition
hemorrhagic symptoms)
 Most common cause of thrombocytopenia in pregnancy
 Laboratory Features:
4. POSTTRANSFUSION PURPURA (PTP)
 Random platelet counts in pregnant and postpartum
 Rare disorder that typically develops about 1 week
women are slightly higher than normal.
after transfusion of platelet-containing blood
 5% of pregnant women develop mild
products, including fresh or frozen plasma, whole
thrombocytopenia (100,000 to 150,000/μL)
blood, and packed or washed red cells.
 98% of such women having platelet
 Manifested by the rapid onset of severe
counts >70,000/μL.
thrombocytopenia and moderate to severe
hemorrhage that may be life threatening.
 Majority of the cases are results of alloantibody B. Preeclampsia
directed against the platelet antigen P1A1 (HPA – 1a)  Complicates about 5% of pregnancies and typically occurs at
 Involvement of other alloantigens, such as HPA-3a about 20 weeks of gestation.
(Bak), HPA-4 (Pen), and HPA-5b (Br), have also been  Usually becomes evident during second trimester
reported.  Major contributor to maternal and fatal morbidity and
 Most patients with PTP are multiparous middle-aged mortality
women and almost all patients have a history of blood  Characterized by:
transfusion.  Onset of hypertension (200/150 BP) and proteinuria
 Treatment:  Abdominal pain
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 Headache  About twice as many women as men are affected, and it is

 Blurred vision most common in women 30 to 40 years of age.
 Mental function disturbances  Hyaline microthrombi are the characteristic pathologic
 Thrombocytopenia occurs in 15% to 20% of patients feature and are found in multiple organs
with preeclampsia, with 40% to 50% of these patients  Coagulation screening tests and D – dimer assay are NORMAL
progressing to eclampsia (hypertension, proteinuria, in TTP, in contrast to DIC which are abnormal
and seizures).  Four Types of TTP:
 The best treatment of preeclampsia is delivery of the 1. In most patients, TTP occurs as a single acute episode,
infant whenever possible. although a small fraction of these patients may have
 Early reports suggested that in vivo platelet activation recurrence at seemingly random intervals.
may contribute to the development of preeclampsia 2. Second, recurrent TTP occurs in 11% to 28% of TTP
because low-dose aspirin therapy has been shown to patients.
prevent preeclampsia in high-risk patients. 3. Third, certain types of drugs can induce TTP. The primary
agents involved are the thienopyridine agents
C. Eclampsia ticlopidine (Ticlid) and clopidogrel (Plavix), which are
 Defined by the occurrence of acute neurologic used to inhibit platelet function.
abnormalities in a preeclamptic woman during → Ticlopidine seems to cause TTP in about 0.025% of
peripartum period patients, whereas the incidence of
 Connection with thrombocytopenia, in a manner that clopidogrelinduced TTP is approximately four times
blood coagulation is activated and is detected by less
elevated FDG and thrombin – antithrombin process → These common types of TTP generally result from
 Low level of ADAMTS13 is detected autoantibodies that aid in the removal of the
ADAMTS13 (a disintegrin and metalloprotease
with a thrombospondin type 1 motif, member 13)
D. HELLP (Hemolysis, Elevated Liver Enzyme, Low Platelet enzyme or block its function.
Count) Syndrome
4. Fourth, rarely, patients experience chronic relapsing TTP
 Disorder related to preeclampsia/eclampsia and is in which episodes occur at intervals of approximately 3
seen in the peripartum period and defined by the months starting in infancy.
presence of microangiopathic → This form of TTP, known as Upshaw-Shulman
 HA, elevated liver enzymes, and low platelet count syndrome, is hereditary and congenital
 HELLP - Hemolysis, Elevated Liver Enzyme, Low Platelet → It is associated with an autosomal recessive gene
Count mutation that leads to ADAMTS13 dysfunction.
→ Familial chronic relapsing TTP is characterized by
2. HEMOLYTIC DISEASE OF THE NEWBORN (HDN) recurrent episodes of thrombocytopenia with or
 Thrombocytopenia, usually moderate in degree, occurs without ischemic organ damage.
commonly in infants with hemolytic disease of the → TTP usually develops only when clinical conditions
newborn. with increased von Willebrand factor (VWF) levels
 Although the erythrocyte destruction characteristic of (e.g., infection) occur.
this disorder is antibody mediated, the antigens → In this type of TTP, ADAMTS13 activity is nearly
against which the antibodies are directed are not completely deficient.
expressed on platelets.
 Platelets may be destroyed as a result of their  Two Types of TTP: Acquired and Hereditary
interaction with products of red cell breakdown, rather A. Acquired TTP
than their direct participation in an immunologic → Thrombi found most extensively in the heart,
reaction. pancreas, spleen, kidney, adrenal gland, and brain
and are composed mainly of platelets and vWF
3. THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) → Associated with ADAMTS13 deficiency (a
 Sometimes referred to as Moschcowitz syndrome disintegrin – like and metalloprotease with
 Uncommon but not rare thrombospondin motifs) and is found in most cases
 Characterized by: → ADAMTS13 is also decreased in sepsis, DIC, and
 Triad of microangiopathic hemolytic anemia liver disease
(MAHA) → Laboratory Findings:
 Thrombocytopenia  Thrombocytopenia and hemolysis, with the
 Meurologic abnormalities blood smear showing polychromasia,
basophilic stippling, nucleated cells,
 Fever and renal dysfunction (forming a pentad)
schistocytes
can be present
 Platelet counts below 20 x 109/L at first
 MAHA and thrombocytopenia are the most common
presentation
clinical findings
 Reticulocyte count increased
 Diarrhea, anorexia, nausea, weakness, and fatigue, are
present in most patients at the time of diagnosis.  Bone marrow studies reveal erythroid
hyperplasia, increased number of

SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

megakaryocytes and occationally  Associated with a defect in the regulation of complement

microvascular hyaline thrombi activation.
 Screening tests are usually normal and  A number of mutations in complement regulatory proteins
FDP may be slightly increased have been identified.
 Serum lactic dehydrogenase and  Mutations in factor H that impair the control of the
unconjugated concentrations are complement alternative pathway appear to be the most
common but invariably increased common.
 Hemolysis is of the intravascular type:  Although endothelial cells, RBCs, and platelets can be
haptoglobin levels are reduced and activated by complement, the role of each of these cell
hemoglobinuria and hemosiderinuria types in mediating the clinical phenotype is unclear.
usually are present  Eculizumab (Soliris, Alexion) is a humanized monoclonal
 LDH levels and platelet counts are antibody that acts as a C5 terminal complement inhibitor.
sensitive indices of the response of the  Eculizumab has been approved as treatment for patients
disorder to therapy with aHUS.
 Proteinuria and microscopic hematuria
are present in most cases 6. DISSEMINATED INTRAVASCULAR COAGULATION
 Blood urea nitrogen and creatinine are
 A common cause of destructive thrombocytopenia is
normal or slightly elevated
activation of the coagulation cascade (by a variety of agents
or conditions), resulting in a consumptive coagulopathy that
B. Hereditary TTP entraps platelets in intravascular fibrin clots.
→ AKA Schulman – Upshaw syndrome or Chronic  DIC has many similarities to TTP, including MAHA and
Relapsing TTP deposition of thrombi in the arterial circulation of most
→ Rare disorder believed to <1% of the TTP cases organs.
→ In the typical cases, the affected neonated is  Almost same with TTP but thrombi is composed mostly of
born with meconium stain or presents within a Platelets and Fibrinogen (red clots).
few hours after birth with neonatal distress,  Systemic activation of platelets = Thrombosis
jaundice and thrombocytopenia
 Mass consumption of platelets occurs. = Bleeding
→ Hemolysis with schistocyte on blood smears
 Decreased Factors V, VIII and Fibrinogen because of
may be noted
continuous in vivo THROMBIN formation
→ Hereditary TTP responds to 10 – 15 ml of FFP
per kilogram of body weight administered
every 2 to 3 weeks A. Acute DIC
 Rapid platelet consumption
4. HEMOLYTIC UREMIC SYNDROME  Results to severe thrombocytopenia
 HUS is more common than TTP, with an annual  Levels of factor V, factor VIII, and fibrinogen are decreased as
incidence estimated at 2 to 6 per 100,000. a result of in vivo thrombin generation.
 Predominant in 6 months to 4 years children  The test for D-dimer (a breakdown product of stabilized fibrin)
 Caused by Shigella dysenteriae serotypes or almost always yields positive results.
enterohemorrhagic Escherichia coli OH serotypes,  This form of DIC is life-threatening and must be treated
particularly O157:H7 immediately.
 These organisms sometimes can be cultured from stool
specimens. B. Chronic DIC
 The bloody diarrhea typical of childhood HUS is caused  Ongoing, low-grade consumptive coagulopathy.
by colonization of the large intestine with the  Clotting factors may be slightly reduced or normal, and
offending organism, which causes erosive damage to compensatory thrombocytopoiesis results in a moderately
the colon. low to normal platelet count.
 S. dysenteriae produces Shiga toxin, and  D-dimer may not be elevated or may be slightly or
enterohemorrhagic E. coli produces either Shiga-like moderately increased.
toxin-1 (SLT-1) or SLT-2, which can be detected in fecal  Chronic DIC is not generally life-threatening, and treatment
samples from patients with HUS. usually is not urgent.
 Self-limiting
 Cardinal Signs: Hemolytic A., Renal F., and  Mild to moderate thrombocytopenia > Due to kidneys
Thrombocytopenia platelet consumption
 Mild to moderate thrombocytopenia > Due to kidneys
platelet consumption 7. PURPURA FULMINANS
 a unique and devastating thrombotic disorder
5. ATYPICAL HEMOLYTIC UREMIC SYNDROME
 Often acute and fatal
 Life-threatening disease
 Manifests as large irregular areas of blue-black cutaneous
 Extremely rare, progressive disease that often has a bleeding that rapidly progress to necrosis of superficial skin
genetic component. and deeper soft tissues.
 Not associated with an infection  Occurring most commonly in neonates and children
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 Presenting feature of acute sepsis resulting from  Lowering the body temperature to less than 25° C, as is
bacterial infections with commonly done in cardiovascular surgery, results in a
 Neisseria meningitidis transient but mild thrombocytopenia secondary to
 Streptococcus pneumoniae platelet sequestration in the spleen and liver.
 group A and B streptococci  An associated transient defect in function also occurs with
hypothermia.
 Less commonly, Haemophilus influenzas or
Staphylococcus aureus  Platelet count and function return to baseline values on
 In sepsis there is widespread activation of the systemic return to normal body temperature.
inflammatory response, as well as the coagulation and  Thrombocytopenia often follows surgery involving
complement pathways, which leads to increased extracorporeal circulatory devices (such as coronary bypass
bleeding. circuits, ventricular assist devices, and extracorporeal
membrane oxygenation [ECMO]), as a consequence of
 In the neonatal setting, PF may be associated with
damage and partial activation of platelets in the pump.
congenital or acquired deficiencies in protein C (PC)
concentration or activity which promote thrombosis.  Severe thrombocytopenia, marked impairment of platelet
 The principal laboratory features of PF mirror those of function, and activation of fibrinolysis and intravascular
coagulation may develop.
DIC, including prolongation of coagulation times,
thrombocytopenia, hypofibrinogenemia, and increased  Mild thrombocytopenia may be encountered in patients
fibrin degradation products with chronic renal failure, severe iron deficiency,
megaloblastic anemia, postcompression sickness, and chronic
 Treatments:
hypoxia.
 PF with DIC (plasma and platelet transfusions
 Replacement therapy with a human-derived PC
concentrate (Ceprotin) II. THROMBOCYTOSIS
 Intravenous dosing  Thrombocytosis is defined as an abnormally high platelet
 Long-term antithrombotic therapy with PC count greater than 450,000/mL.
replacement alone or in combination with
Coumadin or low-molecular-weight heparin A. REACTIVE THROMBCYTOSIS
(Severe; on going risks of PF)  Elevation in the platelet count secondary to inflammation,
trauma, or other underlying and seemingly unrelated
8. NONIMMUNE DRUG-INDUCED THROMBOCYTOPENIA condition.
 A few drugs directly interact with platelets to cause  Platelet counts between 450,000/mL and 800,000/mL with
thrombocytopenia in a nonimmune manner. no change in platelet function can result from
 Ristocetin - an antibiotic no longer in clinical use, → acute blood loss, splenectomy, childbirth, tissue
facilitates the interaction of VWF with platelet necrosis secondary to surgery, chronic inflammatory
membrane GPIb and leads to in vivo platelet disease, infection, exercise, iron deficiency anemia,
agglutination and thrombocytopenia. hemolytic anemia, renal disorders, and various
 Hematin - used for the treatment of acute intermittent malignancies.
porphyria, may give rise to a transient 
thrombocytopenia that seems to be caused by  Platelet production remains responsive to normal regulatory
stimulation of platelet secretion and aggregation. stimuli (e.g., thrombopoietin, a glycoprotein hormone that is
 Protamine sulfate and bleomycin - may induce produced chiefly in the liver parenchyma and secondarily in
thrombocytopenia by a similar mechanism. the kidney)
 Morphologically normal platelets are produced at a
ABNORMALITIES IN DISTRIBUTION OR DILUTION moderately increased rate.
 A common clinical cause of thrombocytopenia is an  Characterized by unregulated or autonomous platelet
abnormal distribution of platelets. production and platelets of variable size.
 The normal spleen sequesters approximately one third  Examination of the bone marrow from patients with reactive
of the total platelet mass. thrombocytosis reveals a normal to increased number of
megakaryocytes that are normal in morphology.
 Mild thrombocytopenia may be present in any of the
“big spleen” syndromes, where normally produced  Results of platelet aggregation tests induced by various
platelets are physically sequestered. agents usually reveal normal platelet function in reactive
thrombocytosis.
 Common disorders that cause splenomegaly include
end-stage liver diseases causing hepatic cirrhosis and  Reactive thrombocytosis is not associated with thrombosis,
portal hypertension. hemorrhage, or abnormal thrombopoietin levels.
 Other diseases that are associated with splenomegaly  It seldom produces symptoms per se and disappears when
includes: the underlying disorder is brought under control.
 Hodgkin lymphoma
 non-Hodgkin lymphoma Clinical States Resulting in Thrombocytosis
 sarcoidosis, leukemias (e.g., chronic myelogenous Conditions Associated With Reactive Thrombocytosis Blood
leukemia and hairy cell leukemia) loss and surgery
 Gaucher disease Postsplenectomy
Iron deficiency anemia
SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

Reactive thrombocytosis (such as infection or infection plus  An elevated platelet count also may be early evidence of a
surgery) tumor (e.g., Hodgkin disease) and various carcinomas.
Stress (including trauma and postoperative)  Patients with hemophilia often have platelet counts great.
Rebound after myelosuppressive chemotherapy  Kawasaki disease - disorder caused by inflammation of the
walls of small and medium-sized arteries throughout the
body.
Myeloproliferative Disorders Associated With
Thrombocytosis → It is also known as mucocutaneous lymph node
syndrome because it affects lymph nodes, skin, and
Polycythemia vera
mucous membranes in the mouth, nose, and throat.
Chronic myelogenous leukemia
→ Acute febrile illness of infants and young children.
Chronic myelomonocytic leukemia
→ Boys are more likely than girls to develop the disease.
Myelodysplastic syndrome variants (such as myelodysplasia
→ The highest incidence of Kawasaki disease is found in
with del[5q])
Japan.
Primary myelofibrosis
Essential thrombocythemia
5. Exercise-Induced Thrombocytosis
 Strenuous exercise is a well-known cause of relative
1. Reactive Thrombocytosis Associated With Hemorrhage or thrombocytosis and likely is due to the release of platelets
Surgery from the splenic pool or hemoconcentration by transfer of
 After acute hemorrhage, the platelet count may be low plasma water to the extravascular compartment or both.
for 2 to 6 days (if no platelet transfusion) but typically  Normally the platelet count returns to its preexercise
rebounds to elevated levels for several days before baseline level 30 minutes after completion of exercise.
returning to the pre-hemorrhage level.
 Platelet count typically returns to normal 10 to 16 days 6. Rebound Thrombocytosis
after blood loss
 Thrombocytosis often follows the thrombocytopenia caused
by marrow-suppressive therapy or other conditions.
2. Postsplenectomy Thrombocytosis
 “Rebound” thrombocytosis usually peaks 10 to 17 days after
 Removal of the spleen typically results in platelet withdrawal of the offending drug (e.g., alcohol or
counts that can reach or exceed 1 million/mL methotrexate) or after institution of therapy for the
regardless of the reason for splenectomy. underlying condition with which thrombocytopenia is
 The spleen normally sequesters about one third of the associated (e.g., vitamin B12 deficiency).
circulating platelet mass
 Platelet count is elevated for a limited period and B. THROMBOCYTOSIS ASSOCIATED WITH MYELOPROLIFERATIVE
usually does not exceed 800,000/mL, although platelet DISORDERS
counts greater than 1 million/mL are occasionally seen.  Primary or autonomous thrombocytosis is a typical finding in
 Unlike after blood loss from hemorrhage or other four chronic myeloproliferative disorders:
types of surgery, the platelet count reaches a  polycythemia vera
maximum 1 to 3 weeks after splenectomy and remains
 chronic myelogenous leukemia
elevated for 1 to 3 months.
 myelofibrosis with myeloid metaplasia (primary
myelofibrosis)
3. Thrombocytosis Associated With Iron Deficiency Anemia
 essential thrombocythemia
 Mild iron deficiency anemia (IDA) secondary to chronic
blood loss is associated with thrombocytosis in about
50% of cases. 1. Essential Thrombocytopenia
 Thrombocytosis can be seen in severe IDA, but  Essential or primary thrombocythemia (ET), a chronic
thrombocytopenia also has been reported. myeloproliferative neoplasm.
 In some cases of iron deficiency, the platelet count  The most common cause of thrombocytosis and is usually
may be 2 million/mL. After iron therapy is started, the diagnosed by excluding all the causes of reactive
platelet count usually returns to normal within 7 to 10 thrombocytosis.
days.  Characterized by:
 peripheral blood platelet counts exceeding 1 million/mL
4. Thrombocytosis Associated With Inflammation and  uncontrolled proliferation of marrow megakaryocytes
Disease  platelet count may be markedly elevated in other
 Similar to elevations in C-reactive protein, fibrinogen, myeloproliferative disorders (such as myelodysplastic
VWF, and other acute phase reactants, thrombocytosis syndromes)
may be an indication of inflammation.  persistent marked elevation of the platelet count is an
 Thrombocytosis may be found in association with absolute requirement for the diagnosis of ET.
rheumatoid arthritis, rheumatic fever, osteomyelitis,  Clinical Manifestations:
ulcerative colitis, and acute infections.  Hemorrhage
 In rheumatoid arthritis the presence of thrombocytosis  platelet dysfunction
can be correlated with activation of the inflammatory  Thrombosis
process.

SY.ALCANTARA

0 0
HEMATOLOGY LECTURE
TOPIC: Disorders of Primary Hemostasis: Platelet Disorders WEEK 13

 Diagnosis of exclusion, made by ruling out the other

myeloproliferative disorders and systemic
illnesses that produce reactive thrombocytosis.
 Laboratory Findings:
 Platelet size is heterogeneous
 Platelets may be notably clumped on blood films
 Platelets may be agranular or hypogranular and
have a clear, light blue appearance on a routine
Wright-stained film of the peripheral blood
 Presence of giant and bizarrely shaped platelets is
characteristic of myeloproliferative diseases
 Megakaryocyte fragments or nuclei are commonly
encountered in the peripheral blood
 Number and volume of megakaryocytes are
increased in the bone marrow, and they are
predominantly large, show some cellular atypia,
and tend to form clusters
 Treatment:
 Myelosuppresive agents (Melphalan, busulfan)
 Therapeutic plateletpheresis (extremely high plt.
count)
 Pegylated interferon-a
 Anagrelide
 Low-dose aspirin and hydroxyurea
 Ruxolitinib (kinase inhibitor)

SY.ALCANTARA

0 0