Test 6: Platelet Disorders Flashcards
Defined as a plt. count < 1000,000/uL
less than _________ is critical
thrombocytopenia
20,000/ug (cue for transfusion)
Thrombocytopenia may result from …
- Defective production in bone marrow
- Disorders of distribution and dilution
- Destruction of platelets
What is the normal platelet count range?
150-450 x 10^9/L
What can cause defective production in the bone marrow?
- Decreased # of megakaryocytes
-congenital (Fanconi’s anemia, May-Hegglin anomaly, maternal infection) - Ineffective plt production (caused by impaired DNA synthesis
-hereditary thrombocytopenia
-Megaloblastic anemias
Different types of thrombocytopenia
-non-immune
-immune
-disorders of distribution and dilution of plt
-disorders from destruction of plt. (can result in DIC)
examples of non-immune thrombocytopenia
TTP, HUS, and DIC (aka Microangiopathic Thrombocytopenias)
What are the five types of immune thrombocytopenia?
-Idiopathic (or immune) Thrombocytopenia Purpura
-secondary autoimmune (ITP)
-drug-induced (Ex. HIT)
-post-transfusion
-neonatal alloimmune thrombocytopenias (NAIT)
Immune thrombocytopenias are associated with…
-Igs/compliment on plt. surface
OR
-production of specific anti-plt. Abs
-autoimmune bleeding disorder
-most common form of thrombocytopenia (<200,000/yr in US)
Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
Characterized by deposition of Abs that bind to plt. surface (which are destroyed by phagocytosis in spleen and liver) in addition to abnormal B and T cells
Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
-Acute ITP
-Chronic ITP
symptoms of both acute and chronic types of Immune (Idiopathic) Thrombocytopenic Purpura (ITP)?
-petechiae
-ecchymoses
-epitaxis
-menorrhagia
broad range of severity
In ITP, there are no real p.b. abnormalities except for decreased ___________ count.
How is diagnosis made?
platelet
by exclusion
laboratory findings with ITP include…
-increased MPV
-decreased plt. count (<100 x 10^9/uL)
-megakaryocytic hyperplasia
increased bleeding time
-plt-associated IgG
-usually rapid onset in children
-usually follows recovery from viral infection (CMV, rubella, chicken pox) or post-vaccination
-generally self-limiting (remission in 4-6 weeks)
Acute ITP
Plt. count is usually __________with acute ITP
<20,000/mm^3
Treatment for Acute ITP?
usually not needed, but intravenous immunoglobulin (IVIG), plt transfusion, and splenectomy may be needed
-usually occurs in adults (20-50y)
-three times more likely to be found in females
Chronic ITP
-slow, asymptomatic onset
-can be associated with SLE, HIV, or pregnancy-related
-fluctuating course (can last months to years)
Chronic ITP
antibodies target GP IB/IX or GP IIb/IIIa
Chronic ITP
Chronic ITP plt. range
30,000-80,000/mm3
Treatment of ITP?
depends on the severity,
-IVIG is treatment of choice
-prednisone and corticosteroids can be used
Drug-induced Thrombocytopenia can be caused by…
-quinidine/sulfonamide drugs, hapten-dependent antibodies, and drug-induced autoantibodies (>200 drugs responsible)
antibody induced by drug binds to GPIb/IX or GPIIb/IIIa
Quinidine/sulfonamide-induced thrombocytopenia
Occurs when a drug molecule is too small to react by itself, acts as a hapten, and bind to a glycoprotein to form a complex that acts as a complete antigen. Ex: penicillin
Drug-induced Thrombocytopenia:
Hapten-dependent antibodies
Drug-induced Autoantibodies:
Drug-induced thrombocytopenia that is so common it has its own name.
HIT (Heparin-Induced Thrombocytopenia)
Heparin binds to plt. factor ____
What does this cause?
4
-Circulating molecule released from plt’s alpha granules that binds
to heparin
This heparin-PF4 complex attaches to plt. and causes development of an anti-heparin/PF4 An*. Plt is destroyed when complex gets flagged by an Ab
-plt also gets activated, and will aggregate with other plts. causeing sudden deadly thromboemboli (with even further plt. consuption.)
Why is future use of heparin contraindicated with HIT.
–inlvoleves activation of coagulation system and thrombosis
-LMWH can trigger HIT but at a much lower risk
HIT is assayed using….
-Immunoassay for HIT antibody
-ELISA for heparin/anti-PF4 Abs
-Plt. aggregation using heparin
What is the therapy for HIT?
alternative anticoagulants after Protamine Sulfate treatment
-A rare disorder that develops about 1 week after transfusion of blood products, usually affecting females
-severe thrombocytopenia and moderate to severe hemorrhage that could be life-threatening
Post-transfusion Purpura
Post-transfusion Purpura:
alloantibodies to antigens on the plt or plt membranes of the transfused blood product….. alloantibody against ______ antigen.
HPA-1b
*subsequent transfusion will not increase plt count
with Post-transfusion Purpura, pt. is called “_______________________”.
refractory to plt. transfusion
What is the treatment for Post-transfusion Purpura?
IVIG
same as HDN (Hemolytic Disease of the Newborn), only with plts.
Neonatal Alloimmune Thrombocytopenia (NAIT)
caused when Mom lacks plt. Ag that fetus has, so Mom makes Ab against it. Then this IgG Ab crosses the placenta to destroy the fetal plts.
Neonatal Alloimmune Thrombocytopenia (NAIT)
With Neonatal Alloimmune Thrombocytopenia (NAIT), the majority of alloantibodies target _________.
Severity ranges from mild to life-threatening
GPIIb/IIIa
Non-Immune Thrombocytopenia results from…
-Plt. exposure to nonendothelial surface from activation of coagulation system
OR
-Plt. consumption by vascular injury-DIC, TTP, and Themolytic-uremic Syndrome all can lead to both hemorrhagic and thrombotic* episodes.
caused by excessive deposition of plt aggregates in renal and cerebral vessels (Vascular wall dysfunction*, disrupting the inert basement membrane that leads to platelet aggregation)
Thrombotic Thrombocytopenic Purpura (TTP)
who is more likely to get Thrombotic Thrombocytopenic Purpura (TTP)?
3 times more common in women than men
TTP is present with…
microangiopathic hemolytic anemia (MHA), thrombocytopenia, neurological symptoms, fever, and renal disease.
What organs are typically affected by TTP?
heart, brain, pancreas, and adrenals
TTP:
Normally, ultra-large vWF molecules (ULVWF) are cleaved by ______________ (a disintegrin and metalloprotease with thrombospondin type 1) as the ULVWF molecules are synthesized and released.
ADAMTS13
When ADAMTS13 is deficient, the ULVWF induces…
agglutination and formation of thrombi
TTP peripheral blood smear…
-marked decrease in plt
-RBC polychromasia
-RBC fragmentation
-nRBCs may be present
Treatment for TTP?
plasma exchange using FFP or cryo-poor plasma = lacking most fib., fibronectin, and vWF
-clinically resembles TTP, but occurs in children (6 m0-4 years) and is self-limiting
Hemolytic-uremic syndrome (HUS)
90% of Hemolytic-uremic syndrome (HUS) is caused by…
Shigella or E. coli organisms
Hemolytic-uremic syndrome (HUS) is present with…
hemolytic anemia, renal failure, thrombocytopenia, neurologic manifestations
treatment for Hemolytic-uremic syndrome (HUS)?
supportive care and plasma exchange if necessary
What are the lab findings with HUS?
-Decreased Hgb
-elevated retic count
-schistocytes
Thrombocytosis is a plt count over ___________. With over ______ plt seen per 100x feild.
450,000/uL, 23
Is primary or secondary Thrombocytosis more common?
secondary
Essential (Primary) Thrombocythemia is characterized by uncontrolled ______________ production and _____ ploriferation.
megakaryocyte, plt
30% of RARS pt have _____________.
thrombocytosis
-plt. count is usually greater than 1,000,000/uL
-plt. aggregation and morphology are abnormal*
Essential (Primary) Thrombocythemia
Essential (Primary) Thrombocythemia:
abnormal plt aggregation seen with ___________, ____________, and ______________.
epinephrine, ADP, Collagen
Secondary (Reactive) Thrombocytosis is a secondary response seen with…
-acute blood loss
-childbirth
-infection
-B.M. recovery
-alcohol withdrawal
-severe iron deficiency anemia
This is N. post-op phenomenon?
What is often given post-op to combat thrombotic tendency brought on my secondary thrombocytosis
baby asprin
-plt. count is around 450,000-800,000/uL with not change in plt function
-aggregation and morphalogy are normal
Secondary (Reactive) Thrombocytosis
*more common
Qualitative plt. disorders can be inherited or acquired. What are common symptoms?
-menorrhagia
-bilateral petechiae and purpura
-epistaxis
-post-op bleeding
with qualitative plt. disorders, ________ hemostasis is almost always okay.
secondary
-usually have normal plt. count = functional disorder
-plts. will clot eventually! (rare exception is severe hemorrhagic case of Glanzmann’s Thrombasthenia)
two plt. adhesion disorders?
-Bernard-Soulier Disease
-Glanzmann Thrombasthenia
Disorders of plt. secreation?
-Defects in dense granules
-Hermansky-Pudlak Syndrome
-Chediak-Higashi syndrome
-Wiskott-Aldrich Syndrome
-Storage Pool Disease
-Defects in alpha granules
-Gray Plt. Syndrome
-Thromboxane disorders
Functional plt. disorder that may appear similar to ITP (i.e., thrombocytopenia, and giant plts)
Bernard-Soulier (Giant Platelet) Syndrome
what is the autosomal recessive disorder in which the GpIb receptor missing from plt. surface?
this causes plts not to bind well to what?
Bernard-Soulier (Giant Platelet) Syndrome
vWF
Bernard-Soulier (Giant Platelet) Syndrome causes ___________ adhesion to subendothelium and thus __________ efficiency of primary hemostasis.
decrased, decreased
Bernard-Soulier Syndrome plt. do not respond to _________ and have diminished response to ___________.
ristocetin, thrombin
*some get as big as lymphs
MPV is ________ with BSS.
increased
Bernard-Soulier (Giant Platelet) Syndrome shows absent aggregation with ristocetin (that does NOT correct with…..
normal plasma addition
*resembles vWD, but vWD corrects with normal plasma
Bernard-Soulier (Giant Platelet) Syndrome has mod-severe thrombocytopenia, giant platelets, and ____________ platelet function.
abnormal
treatment for BSS?
plt. transfusions can be helpful (but can cause alloimmunization)
-rare autosomal recessive disorder
-plts appear normal in number and appearance but have defective plt. receptor Gp2b3a (a result of >70 mutations)
-plt is unable to bind to Fbg
Glanzmann Thrombasthenia
plts. use Fbg to help them stick together in 1st and 2nd wave of aggregation. This means Glanzmann Thrombasthenia plts. cant bind to each other ___________.
Adhesion and secretion is normal with GT.
securely
Lab results for Glanzmann Thrombasthenia?
-marked prolonged bleeding time
-normal plt count and morphology
-poor clot retraction (old test)
-lack of response in plt aggregation (except when ristocetin is used, vWF binding to platelets is normal)
Treatment for Glanzmann Thrombasthenia?
-plt transfusions
-hormonal therapy
-recombinant factor VIIa
-bone marrow transplants
Inclove abnormal ADP release that can be due to:
-lack of granules
-deficient quantity of ADP stored in granules
-impaired secretion of normal granular contents.
Disorders of plt secretion (Storage Pool Disease)
What is the classic aggregation result for Storage Pool Disease?
primary wave is normal, BUT secondary wave is abnormal (decreased or absent) to ADP, epinephrine, and decreased response to collagen. Normal response to ristocetin.
Storage Pool Disease will have a _____________ bleeding time.
prolonged
Deficiencies of Dense Granules:
(decreased ATP stores = ______________ disorders)
mild bleeding
-caused by an autosomal recessive gene mutation
-has partial ocluocutaneous albinism, impaired vision, bruises easily, and difficulty clotting.
Hermansky-Pudlak Syndrome
Hermansky-Pudlak Syndrome:
Has 7 known subtypes = ____________ mild bleeding tendency.
lifelong
-caused by lack of dense granules (alpha granules are okay)
Hermansky-Pudlak Syndrome
Hermansky-Pudlak Syndrome:
Marked dilation of __________________ -“Swiss cheese plt.”
open or surface-connected canalicular system
Very rare-seen primarily in Puerto Ricans; typically fatal by middle age.
Hermansky-Pudlak Syndrome
usually the worst of the qualitative inherited stroage pool diseases due to severity of bleeding
Hermansky-Pudlak Syndrome
rare autosomal recessive disorder with a high infant mortality rate due to recurrent bacterial infection
Chediak-Higashi Anomaly or syndrome
Chediak-Higashi Anomaly is a ____________ disease = lifelong mild bleeding tendency.
progressive
characterized by partial oculocutaneous albinism, recurrent infections, neurological problems, and giant lysosomes
Chediak-Higashi Anomaly
unusual because also seen in other species
and also have thrombocytopenia and neutropenia
Chediak-Higashi Anomaly
Chediak-Higashi Anomaly is a mutation of the _______ gene- cytoplasmic granules tend to….
LYST
fuse in all cells.
-sex-linked disorder (boys seldom survive adolescence
-lifelong bleeding tendency
Wiskott-Aldrich Syndrome (WAS)
-very small plt, thrombocytopenia, and severe immune complications resulting from declining T cell quality and quantity.
Wiskott-Aldrich Syndrome (WAS)
What is the classic symptomatic triad of Wiskott-Aldrich Syndrome (WAS)?
eczema, recurrent infections, and thrombocytopenia
What causes thrombocytopenia with Wiskott-Aldrich Syndrome (WAS)?
by increased splenic sequestration, and destruction of defective plts. and ineffective thrombopoiesis
Wiskott-Aldrich Syndrome and Chediak-Higashi Anomaly have decreased _______ stores.
ADP
-lifelong mild bleeding tendency
-lack of alpha granules that make plts appear agranular
-characterized by large, blue-grey pts. on p.b. smear
Gray Platelet Syndrome
due to NBEAL2 gene mutation
Gray Platelet Syndrome
Gray Platelet Syndrome:
plt aggregation assays are…..
normal with mild clinical manifestations
what is also termed “aspirin-like defects”
Thromboxane Pathway Disorders
Thromboxane Pathway Disorders:
Contents of alpha and dense granules are normal, but ADP release or secretion is impaired due to…
-defects in the release of arachidonic acid from plt. p.m. phospholipids (Phospholipase A2 deficiency)
-Thromboxane (TXA2) synthesis deficiency
produces a plt aggregation pattern similar to that of dense granules deficiency.
Thromboxane Pathway Disorders
Thromboxane Pathway Disorders:
Classic aggregation result: primary wave is normal but…
secondary wave is abnormal (decreased or absent) to ADP, epinephrine, and decreased response to collagen.
Normal response to ristocetin.
Where dose aspirin, ibuprofen, and NSAIDs “attack”?
cyclooxygenase (decreases)
Prostaglandins and ___________ are both vital for continued plt. activation.
thromboxane A2
Ibuprofen and Asprin permanently inhibit cyclooxygenase by ___________ it.
acetylating
two acquired qualitative plt disorders?
chronic alcohol use and uremia (dialysis corrects)
alcohol prevents plt. __________ to any roughened areas on endothelium, thereby preventing significant plaque buildup.
aggregation
What are five vascular disorders due to hereditary connective tissue defects?
- Hereditary hemorrhagic Telangiectasia (HHT)
- Acquired (Senile) Purpura
- Henoch-Schonlein Purpura
- Ehlers-Danlos Syndrome
- Pseudoxanthoma Elasticum
characterized by bleeding from telangiectasias (permanent, thin, dilated vascular malformations causing small red lesions);
Hereditary hemorrhagic Telangiectasia (HHT)
most common inherited vascular bleeding disorder
Hereditary hemorrhagic Telangiectasia (HHT)
so-called “allergic” purpura (probably autoimmune) in kids, with skin rash, edema, pruritus, and multifocal joint pain. (Due to IgA, IgE and C3 deposits in vasculature)
Henoch-Schonlein Purpura
May be due to allergies or autoimmune drug-induced, or so-called “senile purpura” (the latter caused by age-related loss of collagen, elastin, and subcutaneous fat to support vessels).
Aquired (Senile) Purpura
heterogeneous group of 11 different connective tissue (collagen) disorders with extreme tissue fragility, causing hyperextensible skin and hypermobile joints.
Ehlers-Danlos Syndrome
defective elastin causes arterioles to be structurally defective
Pseudoxanthoma Elasticum
Petechia, and prolonged bleeding from superficial wounds, are (by themselves) classically characteristic of what other category of disorders?
so these vascular diseases could also be expected to affect primarry ________.
(numerous) plt. disorders
hemostasis
with Glanzzmann’s Thrombasthenia, clot retraction ….
absent or poor
With Asprin-like defects:
adhesin is _______
ADP release is _________
normal, decreased
qualitative plt. disorder:
No GpIb
Bernard-Soulier
qualitative plt. disorder:
defective vWF
vWD (classic)
qualitative plt. disorder:
Defective Gp2b3a
Glanzmann’s Thrombasthenia
qualitative plt. disorder:
decreased ADP stores
Storage pool diseases
qualitative plt. disorder:
Defective TXA2 and thus defective ADP release
Aspirin-Like Defects
In which qualitative plt. defect is there normal adhesion?
only in aspirin-like defects
What is the bleeding time like in qualitative plt disorders?
always increased
Qualitative plt disorders:
what is the plt. count like in these disorders?
always normal
In which qualitative plt. disorder is there abnormal clot retraction?
Glanzmann’s Thrombasthenia
Defective Gp2b3a (Fbg receptor) means secondary wave of aggregation is ineffective and clot cant be consolidated.
With Bernard-Soulier, ristocetin is….
ABSENT (and does NOT correct with normal plasma)
With VWD (plt-type and classic), ristocetin is….
variable! but corrects with normal plasma
Which 2 classes of qualitative plt. disorders typically yield a normal first wave of aggregation, but an abnormal second wave?
Storage Pool Diseases and Aspirin-like defects
Name the four storage pool diseases of plt.
Wiskott-Aldrich
Chediak-Higashi
Hermansky-Pudlak
Gray plt. syndromes
