Chap 37: Qualitative Disorder of Platelets and Vasculature Flashcards
Excessive bruising and superficial (mucocutaneous) bleeding in a patient whose platelet count is normal suggest an
Acquired or congenital disorder of platelet function
Disorders of Platelet Aggregation
- Glanzmann thrombasthenia
- Hereditary afibrinogenemia
- Acquired defects of platelet aggregation (Acquired von Willebrand disease, Acquired uremia)
Disorders of Platelet Adhesion
- Bernard-Soulier syndrome
- Von Willebrand disease
- Acquired defects of platelet adhesion:
(Myeloproliferative and lymphoproliferative disorders, dysproteinemias
Antiplatelet antibodies
Cardiopulmonary bypass surgery
Chronic liver disease
Drug-induced membrane modification)
Disorder of Platelet Secretion
- Storage pool diseases
- Thromboxane pathway disorders
- Hereditary aspirin-like defects (Cyclooxygenase or thromboxane synthetase deficiency)
- Drug inhibition of the prostaglandin pathways
- Drug inhibition of platelet phosphodiesterase activity
Described as bleeding disorder associated with abnormal in vitro clot retraction and a normal platelet count
Glanzmann Thrombasthenia
Is the process by which the volume of a formed clot is reduced through contraction of the intracellular actin-myosin cytoskeleton of activated platelets incorporated in the clot.
Clot retraction
GT is inherited and most frequently seen in population with a high degree of ?
Consanguinity
Hemorrhagic manifestation og GT includes:
petechiae, purpura, menorrhagia, gastrointestinal bleeding, and hematuria
Biochemical lesion responsible for the disorder is a deficiency or abnormality of what platelet membrane glycoprotein
(GP) IIb/IIIa (integrin aIIb3) complex,
A membrane receptor capable of binding fibrinogen, von Willebrand factor (VWF), fibronectin, and other adhesive ligand
GP IIb/IIIa
T/F: Patients with type 2 GT disease are less affected by abnormal clot retraction and fibrinogen binding.
TRUE
Genetic mutations of GT are distributed widely over what genes?
ITGA2b or ITGb3
What chromosome codes for GP IIb/IIIa
Chromosome 17
Lab feature for GT
Normal Platelet count
Normal platelet morphology
Lack platelet aggregation
Normal ristocetin-induced binding of VWF
One of the few forms of platelet dysfunction in which hemorrhage is severe and disabling.
Thrombasthenia
Patients with GT should avoid
Anticoagulants and antiplatelet agents such as aspirin and nonsteroidal anti-inflammatory drugs
Treatment to control or prevent bleeding caused by GT
- Hormonal therapy (norethindrone acetate)
- Antifibrinoytic therapy
- Recombinant Factor VIIa
A rare disorder of platelet adhesion that usually manifests in infancy or childhood with hemorrhage characteristic of defective platelet function: ecchymoses, epistaxis, and gingival bleeding
Bernard-Soulier (Giant Platelet) Syndrome
BSs in inherited as an autosomal recessive in what glycoprotein complex?
GP Ib/IX/V
Essential to normal function because it contains binding sites for VWF and thrombin.
GP Iba
The most frequent forms of BSS involve defects in
GP Iba
The clotting activity of this factor is reduced in BSS
Factor VIII
Lab features of BSS
- Normal aggregation responses to ADP, epinephrine, collagen and arachidonic acid
- Do not respond to ristocetin
- Diminished response to thrombin
Platelets used to treat BSS should be _ to reduce alloimmunization
Pre-storage leukoreduced
BSS is characterized by
Large platelets and thrombocytopenia
Platelet structure has abnormal microtubule distribution
May-Hegglin anomaly
Platelets are spherical and have a prominent surface-connected canalicular system
Epstein syndrome
Most common of the hereditary platelet function defects. Patients with these disorders present with mucocutaneous hemorrhage and hematuria, epistaxis, and easy and spontaneous bruising
Storage pool and release reaction defects
Dense granules are the storage site of? (4)
- Serotonin
- Nucleotide (ADP and ATP)
- Calcium
- Pyrophosphate
T/F: Dense granule deficiency does not typically result in a serious hemorrhagic problem. Bleeding is usually mild and most often is limited to easy bruising
TRUE
Substances that induce a primary wave of aggregation, but a secondary wave is missing
Epinephrine and Low-dose ADP
Examples of Dense Granule Deficiency
- Hermansky-Pudlak syndrome
- Chédiak-Higashi syndrome
- Wiskott-Aldrich syndrome
- Thrombocytopenia–absent radius (TAR) syndrome
Autosomal recessive disorder characterized by tyrosinase- positive oculocutaneous albinism, defective lysosomal function in a variety of cell types, ceroid-like deposition in the cells of the reticuloendothelial system, and a profound platelet dense granule deficiency
Hermansky-Pudlak syndrome
Mutations in at least _ genes individually can give rise to Hermansky-Pudlak Syndrome
Seven
Can be used to treat skin wounds that fail to spontaneously clot
Thrombin-soaked Gelfoam
The unique morphologic abnormality describe in patient with Hermansky-Pudlak syndrome
marked dilation and tortuosity of the surface-connecting tubular system (Swiss Cheese Platelet)
Characterized by partial oculocutaneous albinism, frequent pyogenic bacterial infections, giant lysosomal granules in cells of hematologic and nonhematologic origin, platelet dense granule deficiency, and hemorrhage.
Chédiak-Higashi syndrome
Gene for the Chédiak-Higashi syndrome protein is lo- cated on
Chromosome 1
This disorder progresses to an accelerated phase that is marked by lymphocytic proliferation in the liver, spleen, and marrow with macrophage accumulation in tissues
Chédiak-Higashi syndrome
Disease caused by mutations in the WAS gene on the short arm of the X chromosome Xp11.23 that encodes for a 502-amino acid protein
Wiskott-Aldrich syndrome (WAS)
Plays a crucial role in actin cytoskeleton remodeling
Wiskott-Aldrich syndrome protein (WASp)
classic form of WAS, characterized by susceptibility to infections associated with immune dysfunction, with recurrent bacterial, viral, and fungal infections, microthrombocytopenia, and severe eczema
Eczema-thrombocytopenia immunodeficiency syndrome
Individuals with WAS lack the ability to make anti- polysaccharide antibodies, which results in a propensity for
Pneumoccocal sepsis
A diagnostic feature of WAS platelets
- Dense granules is decreased
- Small platelets (microthrombocytes)
Other than in WAS, such small platelets are seen only in association with
TORCH (toxoplasma, other agents, rubella virus, cytomegalovirus, herpesvirus) infections
Other lab features of WAS
- Decreased aggregation in response to ADP, collagen and epinephrine
- Lack of 2ndary wave of aggregation
- Normal thrombin
Rare autosomal recessive disorder characterized by the congenital absence of the radial bones (the most pronounced skeletal abnormality), numerous cardiac and other skeletal abnormalities, and thrombocytopenia
Thrombocytopenia with absent radii syndrome( TAR)
This cell may be decreased in number, immature, or normal in TAR
Marrow megakaryocytes
The storage site for proteins produced by the megakaryocyte (e.g., platelet-derived growth factor, thrombospondin, and platelet factor 4)
Alpha granules (a-granules)
How may a-granules are found per platelet? Hence these are responsible for the granular appearance of platelets on stained blood films
50-80 a-granules
Rare disorder characterized by the specific absence of morphologically recognizable a-granules in platelets
Gray platelet syndrome
Characterized by lifelong mild bleeding tendencies, moderate thrombocytopenia, fibrosis of the marrow, and large platelets whose gray appearance on a Wright-stained blood film
Gray platelet syndrome
This has been used to control bleeding in patient with Gray platelet syndrome
Cryoprecipitate
Shorten the bleeding
time test and has been used as successful prophylaxis during a dental extraction procedure.
Desmopressin acetate
An autosomal dominant bleeding disorder that results from a deficiency of multimerin (a multimeric protein that is stored complexed with factor V in a-granules).
Quebec platelet disorder
Converted to intermediate prostaglandins by cyclooxygenase and to thromboxane A2 by thromboxane synthase
Arachidonic acid
Several acquired or congenital disorders of platelet secretion can be traced to structural and functional modifications of
Arachidonic acid pathway enzymes
Required for storage granule secretion and maxi- mal platelet aggregation in response to epinephrine, ADP, and low concentrations of collagen.
Thromboxane A2
Hereditary absence or abnormalities of the components of the thromboxane pathway are usually termed
Aspirin-Like defects
One of the collagen receptors in the platelet membrane
A2B1 (GP Ia/IIa) integrin
Are members of the seven-transmembrane domain (STD) family of G protein-linked receptors
P2Y1 and P2Y12
The receptor that is linked to an ion channel that facilitates calcium ion influx.
P2X1
Is thought to mediate calcium mobilization and shape change in response to ADP
P2Y1
Asociated with decreased platelet activation and aggregation in response to epinephrine are known
Congenital defect of the a2-adrenergic (epinephrine) receptor
Defects represent a heterogeneous group of disorders in which all elements of the thromboxane pathway are normal, but insufficient calcium is released from the dense tubular system
Calcium mobilization
A very rare autosomal recessive disorder of calcium-induced membrane phospholipid scrambling (necessary for coagulation factor assembly) and thrombin generation on platelets.
Scott syndrome
In Scott syndrome, platelet secrete and aggregate normally but do not transport
Phosphatidylserine and phosphatidylethanolamine
Asymmetry of resting platelet is maintained by the enzyme
Aminophospholipid translocase
Autosomal dominant disorder characterized by a mild bleeding tendency due to platelet dysfunction, thrombocytopenia, anemia, functional asplenia, and other constitutive disorders
Stormorken syndrome
Platelets are always in an “activated” state and express phosphatidylserin
Stormorken Syndrome
Most frequent cause of acquired platelet dysfunction is
Drug ingestion
A single _ can irreversibly acetylate 90% of the platelet cyclooxygenase
200-mg dose of aspirin
Endothelial cells also produce this another potent platelet inhibitor
Nitric Oxide (NO)
T/F: Patients who do not respond well to aspirin have worse cardiovascular outcomes than patients who respond well
TRUE
One system that provides measurement of a patient’s response to antiplatelet medication
VerifyNow (IL-Werfen)
Group of drugs that decreases platelet function
ibuprofen, ketoprofen, fenoprofen, naproxen, and sulfinpyrazone.
P2Y12 (ADP) receptor inhibitors
thienopyridine derivatives clopidogrel and prasugrel; their predecessor, ticlopidine; the nucleoside ticagrelor; and the nucleotide mimetic cangrelor
A prodrug that requires conversion to the active drug by the 2C19 (a.k.a. CYP2C19) isoform of P450 in the liver.
Clopidogrel
Third-generation thienopyridine derivative with the same mechanism of action as clopidogrel
Prasugrel
Not a prodrug and therefore does not require bioactivation. Because it is rapidly absorbed
Ticagrelor
a reversible, nucleotide mimetic P2Y12 inhibitor that, like ticagrelor, does not undergo metabolic activation
Cangrelor
Approved for use as an adjunct treatment for reducing the risk of myocardial infarction, repeat coronary intervention, and stent thrombosis in patients undergoing per- cutaneous coronary intervention
Cangrelor
inhibits thrombin-induced platelet aggregation by blocking the ligand-binding site on PAR-1.
Vorapaxar
inhibitor of platelet phosphodiesterase, the enzyme responsible for converting cyclic adenosine monophosphate (cAMP) to AMP. Inhibition of phosphodiesterase allows the accumulation of cAMP in the cytoplasm; elevation of cytoplasmic cAMP is inhibitory to platelet function
Dipyridamole
non-b-lactam antibiotic that may inhibit platelet aggregation when high concentrations are present in the blood.
Nitrofurantoin
partially hydrolyzed, branched-chain polysaccharides of glucose
Dextrans
Both drugs are commonly used as plasma ex- pandes
Dextran 70 and Dextran 40
A synthetic glucose polymer with a mean molecular mass up to 450,000 Daltons that is used as a plasma expander.
Hydroxyethyl starch, or hetastarch
Drugs used to regulate cardiovascular function that seem to be able to cause a decrease in platelet secretion and aggregation
Nitroglycerin, nitroprusside, propranolol, and isosorbide dinitrate
Patient taking this may have decreased secretion and aggregation responses
Phenothiazine and tricyclic antidepressant
Chronic myeloproliferative neoplasms (MPNs) include
polycythemia vera, chronic myelogenous leukemia (CML), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia
Patient with MPNs have been reported with having platelets that are
abnormal in shape, decreased procoagulant activity, decreased number of secretory granules and shortened survival
Most common functional abnormalities are
Decreased aggregation and secretion in response to epinephrine, ADP, and collagen
Platelet dysfunction results from coating of the platelet membrane by paraprotein and does not depend on the type of paraprotein present is seen on
IgA myeloma and Waldenstrom macroglobulinemia
The use of _ during cardiac surgery induces thrombocytopenia and a severe platelet function defect
Cardiopulmonary bypass
Reduction in clotting proteins, reduction of proteins in the natural anticoagulant pathways, dysfibrinogenemia, and excessive fibrinolysis are seen on patient with
Liver disease
Commonly accompanied by bleeding caused by platelet dysfunction
Uremia
What acid is present in uremia which is a result of inhibition of the urea cycle
guanidinosuccinic acid (GSA)
An independent cause of prolonged bleeding time, and the severity of anemia in uremic patients correlates with the severity of renal failure
Anemia
Not truly a platelet function disorder, but platelets do not exhibit normal function in the absence or near-absence of fibrinogen
Congenital afibrinogenemia
Can be used to treat bleeding episodes in Congenital afibrinogenemia
Cryoprecipitate or Fibrinogen concentrate
Autosomal dominant, thrombophilic disorder that is associated with venous and arterial thromboembolic events.
Sticky platelet syndrome
Sticky platelet syndrome is characterized by
Hyperaggregable platelets in response to ADP, epinephrine, or both
Is an indicator of abnormally increased platelet reactivity and often accompanies increased sensitivity to platelet agonists
Spontaneous aggregation (aggregation in response to in vitro stirring only)
The esult of in vivo stimulation by thrombin and other agonists resulting in in vivo release of granule contents is called
Acquired storage pool disease (exhausted platelets)
Vascular defect of this disorder is characterized by thin-walled blood vessels with a discontinuous endothelium, inadequate smooth muscle, and inadequate or missing elastin in the surrounding stroma
Hereditary Hemorrhagic Telangiectasia
An almost universal finding, and symptoms almost always worsen with age (seen on Telangiectasia)
Epistaxis
Common in older men and women
Cherry-red hemangiomas
Louis bar syndrome
Ataxia-Telangiectasia
Seen in association with chronic liver disease and pregnancy
Chronic Actinic Telangiectasia
A giant cavernous hemangioma (vascular tumor), thrombocytopenia, and a bleeding diathesis.
Kasabach and Merritt
May become engorged with blood and resemble hematomas.
External Hemangiomas
May be transmitted as an autosomal dominant, recessive, or X-linked trait. May be manifested by hyperextensible skin, hypermobile joints, joint laxity, fragile tissue and bleeding tendency
Ehlers-Danlos Syndrome
This disorder generally can be ascribed to defects in collagen production, structure, or cross- linking, with resulting inadequacy of the connective tissues
Ehlers-Danlos syndrome
Applied to a group of nonthrombocytopenic purpuras characterized by apparently allergic manifestations, including skin rash and edema
Allergic purpura or anaphylactoid purpura
Condition where acute IgA-mediated disorder with widespread generalized vasculitis involving the skin, joints, kidneys, gastrointestinal tract, and, less commonly, the lungs.
Henoch-Schönlein purpura
Has been associated with cer- tain foods and drugs, cold, insect bites, and vaccination
Allergic purpura
Henoch-Schönlein purpura is primarily a disease of children, occurring most commonly in children
3 to 7 years of age
High concentrations of __ can cause severe hemorrhagic manifestations as a result of a combination of hyperviscosity and platelet dysfunction
Paraprotein
A fibrous protein consisting of rigid, linear, non- branching, aggregated fibrils approximately 7.5 to 10 nm wide and of indefinite length
Amyloid
The deposition of abnormal quantities of amyloid protein in tissues, may be primary or secondary, and localized or systemic
Amyloidosis
Occurs more commonly in elderly men than in women and is due to a lack of collagen support for small blood vessels and loss of subcutaneous fat and elastic fibe
Senile Purpura
Purpura associated with drug-induced vasculitis occurs in the presence of functionally adequate platelets
Drug-Induced Vascular Purpuras
