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The laboratory diagnosis of platelet disorders: an algorithmic approach. (CAP Laboratory Improvement Programs).



Platelets are small (2-[micro]m-diameter), nonnucleated blood cells produced in the bone marrow from megakaryocytes. Platelets are activated rapidly after blood vessel injury or blood exposure to the artificial surfaces of implanted devices, and they are a crucial component of the primary hemostatic hemostatic /he·mo·stat·ic/ (he?mo-stat´ik)
1. causing hemostasis, or an agent that so acts.

2. due to or characterized by stasis of the blood.


he·mo·stat·ic
adj.
 response. In their inactivated inactivated

rendered inactive; the activity is destroyed.


inactivated viruses
treated so that they are no longer able to produce evidence of growth or damaging effect on tissue.
 state, platelets are roughly discoid discoid /dis·coid/ (dis´koid)
1. disk-shaped.

2. a dental instrument with a disklike or circular blade.

3. a disk-shaped dental excavator designed to remove the carious dentin of a decayed tooth.
 in shape and contain cytoplasmic organelles, cytoskeletal cy`to`skel´e`tal   

a. 1. (Cell Biology) Of or pertaining to the cytoskeleton; as, cytoskeletal microtubules s>.
 elements, invaginating open-canalicular membrane systems, and platelet-specific granules Granules
Small packets of reactive chemicals stored within cells.

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, called alpha and dense granules. Platelets have numerous intrinsic glycoproteins embedded in the outer surface of their plasma membrane that are receptors for ligands ranging from fibrinogen Fibrinogen

The major clot-forming substrate in the blood plasma of vertebrates. Though fibrinogen represents a small fraction of plasma proteins (normal human plasma has a fibrinogen content of 2–4 mg/ml of a total of 70 mg protein/ml), its conversion
, collagen, thrombin thrombin: see blood clotting. , and thrombospondin to von Willebrand factor von Willebrand factor (vWF)
A protein found in the blood that is involved in the process of blood clotting.

Mentioned in: Von Willebrand Disease


von Willebrand factor
 (VWF vWF von Willebrand's factor.
von Willebrand factor (vWF)
A protein found in the blood that is involved in the process of blood clotting.

Mentioned in: Von Willebrand Disease
) and fibronectin. (1-3) Platelets promote hemostasis by 4 interconnected mechanisms: (1) adhering to sites of vascular injury or artificial surfaces, (2) releasing compounds from their granules, (3) aggregating together to form a hemostatic platelet plug, and (4) providing a procoagulant procoagulant /pro·co·ag·u·lant/ (-ko-ag´ul-int)
1. tending to promote coagulation.

2. a precursor of a natural substance necessary to coagulation of the blood.
 surface for activated coagulation coagulation (kōăg'ylā`shən), the collecting into a mass of minute particles of a solid dispersed throughout a liquid (a sol), usually followed by the precipitation or  protein complexes on their phospholipid phospholipid (fŏs'fōlĭp`ĭd), lipid that in its simplest form is composed of glycerol bonded to two fatty acids and a phosphate group.  membranes (Figure 1).

[FIGURE 1 OMITTED]

Platelet adhesion to the subendothelium is the initial step in platelet activation. The subendothelium is composed of extracellular matrix proteins, such as collagen, fibronectin, VWF, thrombospondin, and laminin laminin
(lam´n
, (4) many of which are ligands for receptors on the platelet surface. These adhesive proteins are exposed when the endothelial endothelial /en·do·the·li·al/ (-the´le-al) pertaining to or made up of endothelium.
Endothelial
A layer of cells that lines the inside of certain body cavities, for example, blood vessels.
 layer is disrupted. Because of the large number of extracellular matrix proteins and a high density of platelet surface receptors, platelet adhesion to areas of vascular injury is extremely rapid. VWF, a large, multimetric protein secreted into the extracellular matrix from endothelial cells, facilitates platelet adhesion by binding to platelet surface glycoprotein glycoprotein (glī'kōprō`tēn), organic compound composed of both a protein and a carbohydrate joined together in covalent chemical linkage.  Ib/IX/V, especially at high shear rates. (5-7) Platelets can also adhere to vascular wall-associated fibrin fibrin: see blood clotting.  or fibrinogen through interaction with platelet surface glycoprotein IIb/IIIa. (8,9)

After adhering to the subendothelium, platelets undergo a cytoskeletal activation that leads to a shape change with development of pseudopods. Intracellular signaling processes lead to increased cytoplasmic calcium and then initiate a secretory secretory /se·cre·to·ry/ (se-kre´tah-re) (se´kre-tor?e) pertaining to secretion or affecting the secretions.

se·cre·to·ry
adj.
Relating to or performing secretion.
 release reaction, whereby products from the alpha granules (platelet factor 4, [beta]-thromboglobulin, thrombospondin, platelet-derived growth factor platelet-derived growth factor
n.
A substance in platelets that is mitogenic for cells at the site of a wound, causing endothelial proliferation.
, fibrinogen, VWF) and dense granules (adenosine diphosphate [ADP (1) (Automatic Data Processing) Synonymous with data processing (DP), electronic data processing (EDP) and information processing.

(2) (Automatic Data Processing, Inc., Roseland, NJ, www.adp.
], serotonin) are released into the surrounding milieu. (10) The granule granule, in astronomy: see photosphere.  membranes contain many integral glycoproteins on their inner leaflet, such as P-selectin (CD62p) in the alpha granule and gp53 (CD63) in the lysosome lysosome

Membrane-enclosed organelle found in all eukaryotic cells (see eukaryote) that is responsible for the cell's digestion of macromolecules, old cell parts, and microorganisms.
, which become expressed on the outer platelet membrane after the release reaction. (11) The release of ADP from the dense granules, together with calcium mobilization, leads to a conformational change of the fibrinogen receptor, the glycoprotein IIb/IIIa receptor complex (integrin integrin /in·te·grin/ (in´te-grin) any of a family of heterodimeric cell adhesion receptors, each consisting of an a and a ß polypetide chain, that mediate cell-to-cell and cell-to–extracellular matrix interactions.  [[alpha].sub.IIb][[beta].sub.3]). (12) This conformational change of the fibrinogen receptor initiates the process of aggregation, whereby a glycoprotein IIb/IIIa receptor on one platelet is bound in a homotypic fashion to the same receptor on adjacent platelets via a central fibrinogen molecular bridge. Beside ADP, other agonists, such as epinephrine, thrombin, collagen, and platelet-activating factor, can initiate platelet aggregation by interaction with membrane receptors. This platelet release reaction and aggregation lead to the recruitment of many other platelets to the vessel wall with the formation of a hemostatic platelet plug.

Activated platelets also play a vital procoagulant role that serves as a link between platelet function and coagulation activation. Platelet membrane phospholipids undergo a rearrangement during activation with a transfer of phosphatidyl serine serine (sĕr`ēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer appears in mammalian protein.  from the inner table to the outer table of the platelet membrane, providing a binding site for phospholipid-dependent coagulation complexes that activate both factor X and prothrombin prothrombin

Carbohydrate-protein compound in plasma essential to coagulation. In response to bleeding, a complex series of clotting-factor interactions leads to its conversion by thromboplastin to thrombin, which transforms fibrinogen in plasma into fibrin.
. (13)

LABORATORY TESTS USED IN THE EVALUATION OF PLATELET FUNCTION

Clinical History

A careful clinical and family bleeding history should be taken before beginning a laboratory evaluation of platelet function. The history should include an assessment of the duration, pattern, and severity of bleeding problems, including whether the bleeding is spontaneous or associated with trauma or surgery. A lifelong bleeding diathesis may suggest a congenital platelet dysfunction, but an onset in adulthood does not necessarily exclude a congenital problem. In obtaining a history of bleeding pattern, it is necessary to determine whether a true hemorrhagic Hemorrhagic
A condition resulting in massive, difficult-to-control bleeding.

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hemorrhagic

pertaining to or characterized by hemorrhage.
 disorder exists. In this regard, it is often helpful to assess if the bleeding is out of proportion to the degree of trauma, or whether blood transfusions were required for relatively minor surgical procedures, such as tooth extractions.

Platelet-mediated bleeding disorders usually result in a mucocutaneous mucocutaneous /mu·co·cu·ta·ne·ous/ (-ku-ta´ne-us) pertaining to or affecting the mucous membrane and the skin.

mu·co·cu·ta·ne·ous
adj.
Of or relating to the skin and a mucous membrane.
 bleeding pattern, with ecchymosis ECCHYMOSIS, med. jur. Blackness. It is an extravasation of blood by rupture of capillary vessels, and hence it follows contusion; but it may exist, as in cases of scurvy, and other morbid conditions, without the latter. Ryan's Med. Jur. 172. , petechiae Petechiae
Tiny purple or red spots on the skin associated with endocarditis, resulting from hemorrhages under the skin's surface.

Mentioned in: Endocarditis, Hantavirus Infections, Hemorrhagic Fevers, Idiopathic Thrombocytopenic Purpura

, purpura purpura

Presence of hemorrhages in the skin, often associated with bleeding from natural cavities and in tissues. Major causes include damage to small artery walls (as in vitamin deficiency or allergic reaction) and platelet deficiency (in association with such disorders as
, epistaxis epistaxis /ep·i·stax·is/ (-stak´sis) nosebleed; hemorrhage from the nose, usually due to rupture of small vessels overlying the anterior part of the cartilaginous nasal septum.

ep·i·stax·is
n.
, and gingival gingival (jin´jv  bleeding commonly observed. (4) This pattern is in contrast to that observed with coagulation protein disorders, in which deep tissue bleeding and hemarthroses are more common. Von Willebrand disease Von Willebrand Disease Definition

Von Willebrand disease is caused by a deficiency or an abnormality in a protein called von Willebrand factor and is characterized by prolonged bleeding.
, an abnormality of VWF, has bleeding symptoms very similar to platelet dysfunction, and evaluation for von Willebrand disease should be included in the initial evaluation of a possible platelet disorder. (14) Bleeding diatheses due to vascular malformations may give a bleeding pattern similar to platelet disorders, but is often more focal than diffuse. Acquired purpuras, such as those seen with disseminated intravascular coagulation disseminated intravascular coagulation
n.
Abbr. DIC A hemorrhagic disorder that occurs following the uncontrolled activation of clotting factors and fibrinolytic enzymes throughout small blood vessels, resulting in tissue necrosis and
, vasculitis Vasculitis Definition

Vasculitis refers to a varied group of disorders which all share a common underlying problem of inflammation of a blood vessel or blood vessels. The inflammation may affect any size blood vessel, anywhere in the body.
, or infections, can usually be distinguished from platelet dysfunction, because platelet disorders usually cause bleeding from mucous membranes ("wet" purpura), whereas vascular purpura is usually confined to the skin ("dry" purpura). (15)

Many drugs and foods can affect platelet function (Table 1), so a complete drug history should be obtained. (16) It is important to remember that aspirin, an irreversible inhibitor of platelet function, is an ingredient of many over-the-counter and prescription medications, such as cold or flu remedies. Platelet dysfunction is associated with many systemic disorders, such as renal disease, hepatic failure, connective tissue disorders, myeloproliferative disorders, myelodysplastic disorders, malignancy, and cardiovascular disease. Additionally, some clinical features, such as albinism albinism

Absence of the pigment melanin in the eyes, skin, hair, scales, or feathers. It arises from a genetic defect and occurs in humans and other vertebrates. Because they lack the pigments that normally provide protective coloration and screen against the sun's
, deafness, nephritis nephritis (nəfrī`təs), inflammation of the kidney. The earliest finding is within the renal capillaries (glomeruli); interstitial edema is typically followed by interstitial infiltration of lymphocytes, plasma cells, eosinophils, and a , and susceptibility to infections, may help in the differential diagnosis of the inherited platelet disorders. (17)

Platelet Count and Peripheral Blood Smear

The accepted normal range of the platelet count is generally between 150 to 400 X [10.sup.3]/[micro]L of blood, although values much lower than this can be quite adequate for hemostasis. Many clinicians will refrain from platelet repletion re·ple·tion
n.
1. The condition of being fully supplied or completely filled.

2. A state of excessive fullness.
 in a stable patient until counts drop below 10 to 20 X [10.sup.3]/[micro]L. (18) Initial evaluation of the platelet count must take into consideration any pseudothrombocytopenia. Pseudothrombocytopenia is often due to cold-reacting platelet agglutinins or platelet binding to neutrophils neutrophils (ner·ō·trōˑ·filz),
n.pl white blood cells with cytoplasmic granules that consume harmful bacteria, fungi, and other foreign materials.
 (platelet satellitism). The agglutinins are often seen in patients with high immunoglobulin levels or infections and usually only bind platelets when calcium is chelated che·late  
adj. Zoology
Having chelae or resembling a chela.

n. Chemistry
A chemical compound in the form of a heterocyclic ring, containing a metal ion attached by coordinate bonds to at least two nonmetal ions.
, such as in an EDTA EDTA: see chelating agents.  blood collection tube. (19) A pseudothrombocytopenia associated with the glycoprotein IIb/IIIa antagonist drug abciximab has also been reported. (20) Pseudothrombocytopenia can be diagnosed by examining a peripheral smear, where large aggregates of platelets are observed, often around the feathered edge. A more accurate platelet count can be established by collecting the blood sample in either citrate citrate /cit·rate/ (sit´rat) a salt of citric acid.

citrate phosphate dextrose  (CPD) anticoagulant citrate phosphate dextrose solution.
 or heparin anticoagulants Anticoagulants
Drugs that suppress, delay, or prevent blood clots. Anticoagulants are used to treat embolisms.

Mentioned in: Embolism, Heart Valve Replacement
. Giant platelets observed with macrothrombocytopenia syndromes can give false low platelet counts, because the large platelets may be counted as leukocytes by automated cell counters. (21)

The mean platelet volume Mean Platelet Volume (MPV) is a measurement of the average size of platelets found in blood and is typically included in blood tests. Since the average platelet size is larger when the body is producing increased numbers of platelets, MPV test results can be used to make inferences  (MPV (MusicPhotoVideo) A playlist standard for music, image and video collections introduced in 2002 by the Optical Storage Technology Association (OSTA). An "MPV Writer" is software that creates the playlist, and an "MPV Reader" is software that can discover and read it. ) is an indication of platelet size. Normal MPV ranges are approximately 7 to 11 fL. The MPV can be an indication of platelet turnover, because platelets newly released from the bone marrow are larger and tend to decrease in size with age in the circulation. (22) In patients with rapid turnover, the platelets will, in general, be larger because of the larger size of newly produced platelets. True congenital macrothrombocytopenias usually have uniformly large platelets; often the platelets are at least twice the normal size and may be as large as erythrocytes Erythrocytes
Red blood cells.

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erythrocytes (ē·rithˑ·rō·sīts),
n.pl red blood cells.
. Newer techniques based on messenger RNA detection in platelets (reticulated reticulated /re·tic·u·lat·ed/ (-lat?ed) reticular.

reticulated

reticular.
 platelets) may also be helpful to indicate the rate of thrombopoiesis thrombopoiesis /throm·bo·poi·e·sis/ (-poi-e´sis)
1. thrombogenesis.

2. thrombocytopoiesis.thrombopoiet´ic


throm·bo·poi·e·sis
n.
1.
. (23,24)

Platelet disorders can be associated with varying platelet appearances. In von Willebrand disease, Glanzmann thrombasthenia, and myeloproliferative disorders, the platelets have typical morphologic features, whereas giant platelets are seen in Bernard-Soulier disease and other macrothrombocytopenia syndromes. (17,25) In patients with Wiskott-Aldrich syndrome, the platelets may be small. (26) Platelets in the gray platelet syndrome, an alpha granule deficit, are characteristic for being pale, gray, and hypogranular on a Wright-stained blood smear. (27) Some platelet storage pool disorders (SPDs) may have morphologically normal platelet counts by light microscopy, but may have decreased alpha and/or dense granules by electron microscopy. (28)

Platelet Function Screening Tests or Bleeding Time

In the initial evaluation of platelets, it is desirable to perform a screening test to evaluate platelet function. For nearly a century, the bleeding time was the only platelet function screening test available. (29) The bleeding time is a test that is fraught with variability and involves the creation of a standardized cut in the skin and measurement of the time it takes for bleeding to stop. The initial Duke bleeding time used a small incision in the earlobe ear·lobe or ear lobe
n.
The soft, fleshy, pendulous lower part of the external ear.
, and the similar Ratnoff method uses an incision in the ball of the finger. (29,30) The most commonly used bleeding time is the Ivy bleeding time Ivy bleeding time Hematology A quantitative coagulation assay based on a standardized skin wound, which measures platelet and vascular responses to injury; ↑ in Bernard-Soulier disease, Glanzmann's thrombasthenia, platelet defects–eg, , where a standardized incision is made on the volar volar /vo·lar/ (vo´lar) pertaining to sole or palm; indicating the flexor surface of the forearm, wrist, or hand.

volar
 surface of the forearm with a spring-loaded device, using venostatic pressure applied on the upper arm by a sphygmomanometer sphygmomanometer /sphyg·mo·ma·nom·e·ter/ (sfig?mo-mah-nom´e-ter) an instrument for measuring arterial blood pressure.

sphyg·mo·ma·nom·e·ter or sphyg·mom·e·ter
n.
. (31) The bleeding time result depends not only on platelet number and function, but also on fibrinogen concentration, adequate vascular function, orientation and size of the incision, site of the incision, skin quality, skin temperature, operator technique, and patient cooperation.

Although procedural variability affects the bleeding times, bleeding time has been included traditionally as a screening test for suspected bleeding disorders. (32) The bleeding time has little use as a presurgical screen for hemostatic competence in individuals without a history of bleeding and is not useful in discerning platelet dysfunction in thrombocytopenic thrombocytopenic

of the nature of or pertaining to thrombocytopenia.
 patients. (33) Many laboratories have stopped performing the bleeding time test completely because of its variability, poor reproducibility, and lack of correlation with intraoperative bleeding. Newer automated whole blood platelet function screening assays, such as the Platelet Function Analyzer-100 (PFA-100, Dade Behring, Marburg, Germany), are gaining popularity as initial screens for platelet function even though they do not measure the vascular component of the bleeding time. (34) These are described later in the section entitled "Newer Methods of Platelet Evaluation."

Bone Marrow Examination Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called a trephine biopsy) and bone marrow aspiration.  

Examination of the bone marrow can be performed to evaluate both thrombocytopenia Thrombocytopenia Definition

Thrombocytopenia is an abnormal drop in the number of blood cells involved in forming blood clots. These cells are called platelets.
 or thrombocytosis, but it has little role in the evaluation of platelet dysfunction with a normal platelet count. The bone marrow examination may be helpful to ascertain whether thrombocytosis is due to reactive or myeloproliferative disorders. Thrombocytosis can often accompany iron deficiency; evaluation of serum iron studies together with the erythrocyte indices on the complete blood cell count blood cell count,
n an estimation of the number and types of circulating blood cells (e.g., red blood cells [erythrocytic series], white blood cells, differential).
 can usually diagnose the condition and obviate the need for a bone marrow evaluation. In a thrombocytopenic patient, when no other reason for low platelet counts can be determined, the bone marrow examination is useful for determining the presence or absence of megakaryocytes; absence indicates dysfunctional marrow, whereas increased numbers suggest peripheral destruction with attempted bone marrow compensation. Bone marrow examination can also detect myelophthisic disorders, such as acute leukemia, lymphoma, or metastatic malignancy, which could explain a patient's thrombocytopenia.

Platelet Aggregation

Platelet aggregation studies measure the ability of agonists to cause in vitro platelet activation and platelet-platelet binding. Platelet aggregation studies can be performed in whole blood by an impedance technique or in platelet-rich plasma by a turbidimetric technique. (35,36) Platelet aggregation techniques using a microtiter plate or flow cytometer have also been described, but are not widely performed. (37,38) Whole blood platelet aggregation can be combined with studies of dense granule adenosine adenosine /aden·o·sine/ (ah-den´o-sen) a purine nucleoside consisting of adenine and ribose; a component of RNA. It is also a cardiac depressant and vasodilator used as an antiarrhythmic and as an adjunct in myocardial perfusion imaging  triphosphate triphosphate /tri·phos·phate/ (tri-fos´fat) a salt containing three phosphate radicals.

tri·phos·phate
n.
A salt or ester containing three phosphate groups.
 release with a lumiaggregometer. (39) Turbidimetric platelet aggregation studies require platelet-rich plasma prepared from a whole blood specimen. Many factors can affect the platelet aggregation results, such as the platelet count, processing temperature, stirring rate, and processing time (testing should be completed within 4 hours of phlebotomy Phlebotomy Definition

Phlebotomy is the act of drawing or removing blood from the circulatory system through a cut (incision) or puncture in order to obtain a sample for analysis and diagnosis.
). (40) In addition, clinicians who order the tests should advise patients to discontinue using, if possible, any medication that may interfere with the results of the test (Table 1).

In the turbidimetric platelet aggregation assay, platelet aggregation is measured spectrophotometrically by the increase in light transmission after addition of an aggregation agonist. (35) The agonists typically used in the assay include ADP, collagen, arachidonic acid, and epinephrine. Optimal platelet aggregation shows a biphasic bi·pha·sic  
adj.
Having two distinct phases: a biphasic waveform; a biphasic response to a stimulus. 
 pattern for the agonists ADP and epinephrine; the initial increase in aggregation is due to primary aggregation in response to activation of the glycoprotein IIb/IIIa platelet membrane receptor, whereas the second wave of aggregation is the result of platelet degranulation degranulation

the loss of granules; usually refers to the secretory granules in certain cells, e.g. pituitary chromophobes, acidophils and basophils. In basophils and mast cells, it is associated with the release of active substances from the cells and is characteristic of type I
 with recruitment of additional platelet aggregates. Other agonists, such as arachidonic acid, thrombin receptor agonists, and collagen, usually show only a single wave of aggregation.

Another important reagent used in the evaluation of platelet function by aggregation is the antibiotic ristocetin, which facilitates the binding of VWF to the glycoprotein Ib/IX/V complex. (41) Ristocetin-induced platelet aggregation evaluates aggregation after the addition of various concentrations of ristocetin. This dose response allows testing for both increased and decreased sensitivity to ristocetin. For a normal result, the patient requires the presence of both functional VWF and normal glycoprotein Ib/ IX/V, so ristocetin-induced platelet aggregation is an assay that can detect both von Willebrand disease and some platelet dysfunctions, such as Bernard-Soulier syndrome.

Coagulation Testing and von Willebrand Assays

Platelet dysfunction does not directly affect the coagulation proteins; however, the laboratory evaluation of platelet dysfunction should also include some basic coagulation assays, such as the prothrombin time (PT) and activated partial thromboplastin time Activated partial thromboplastin time
Partial thromboplastin time test that uses activators to shorten the clotting time, making it more useful for heparin monitoring.
 (APTT APTT, aPTT activated partial thromboplastin time.

APTT

activated partial thromboplastin time.
), to exclude a coagulopathy as the reason for bleeding.

Von Willebrand disease is not strictly a platelet dysfunction, but it is often considered in the differential diagnosis of bleeding disorders with long bleeding times or abnormal platelet function screening test results. (14) Patients with von Willebrand disease will usually have a family history of a bleeding diathesis and present with mucocutaneous bleeding. The underlying pathologic features of von Willebrand disease are due to decreased levels or defective function of VWF. Von Willebrand disease is protean pro·te·an
adj.
Readily taking on varied shapes, forms, or meanings.



protean

changing form or assuming different shapes.
 in manifestation, but the various types have been grouped into 3 general categories (types 1, 2, and 3). Patients with von Willebrand disease may have decreased VWF antigen, decreased ristocetin cofactor cofactor

An atom, organic molecule, or molecular group that is necessary for the catalytic activity (see catalysis) of many enzymes. A cofactor may be tightly bound to the protein portion of an enzyme and thus be an integral part of its functional structure, or it may
 activity, decreased ristocetin aggregation, decreased factor VIII levels, normal or increased APTT, and increased bleeding times with normal platelet counts. (14)

Newer Methods of Platelet Evaluation

New assay systems to assess platelet function have recently become clinically available. (42) These include the PFA-100, the Ultegra (Accumetrics, San Diego, Calif), and the Plateletworks (Helena, Beaumont, Tex). Most of these devices are small, stand-alone devices that can be used at the patient's bedside or in laboratories that otherwise could not perform platelet function studies.

The PFA-100 is a device that measures platelet-related primary hemostasis in a citrated whole blood specimen. (34) It uses 2 disposable cartridges that contain a membrane with a central aperture (147 [micro]m) coated with aggregation agonists (collagen and epinephrine and collagen and ADP), through which platelets are passed at high shear rates (5000-6000 [s.sup.-1]). The instrument measures the "closure time" required for platelets to adhere to the membrane, aggregate, and occlude (programming) occlude - (Or "shadow") To make a variable inaccessible by declaring another with the same name within the scope of the first.  the aperture. The collagen-epinephrine cartridge is the primary screening cartridge; it detects platelet dysfunction induced by intrinsic platelet defects, von Willebrand disease, or platelet-inhibiting agents. The collagen-ADP cartridge usually produces abnormal results with platelet disorders and von Willebrand disease, but produces a normal closure time with aspirin-like drugs because of the high ADP concentration. Von Willebrand disease, intrinsic platelet dysfunction, and nonaspirin drugs may produce an abnormal closure time with both cartridges. (34) Samples collected for analysis on the PFA-100 are stable for up to 5 hours. The PFA-100 results can be affected by low platelet counts and low hematocrits, but are not affected by heparin. (43)

The Ultegra, a rapid platelet function assay, is an automated turbidimetric whole blood assay designed to assess platelet aggregation based on the ability of activated platelets to bind fibrinogen. (44) Fibrinogen-coated polystyrene microparticles agglutinate ag·glu·ti·nate
v.
1. To clump together; undergo agglutination.

2. To cause substances, such as bacteria, to clump together.

n.
See agglutination.



agglutinate

to stick together and form clumps.
 in whole blood in proportion to the number of available platelet glycoprotein IIb/IIIa receptors. (44) This test uses a whole blood specimen and can be used at the patient's bedside without highly trained laboratory personnel. Because of the use of agonist-activated platelets and fibrinogen-coated microparticles, the Ultegra is designed to measure specifically the effect of glycoprotein IIb/IIIa antagonist drugs, such as abciximab, tirofiban, or eptifibatide, and may be of use to monitor the effect of these potent antiplatelet drugs in the cardiac catheterization laboratory or intensive care unit. (42,45,46) It is not sensitive to drugs such as aspirin or the thienopyridines (clopidogrel and ticlopidine), and it is not designed to detect platelet functional disorders or von Willebrand disease.

Recently, a rapid platelet aggregometer has become available (Plateletworks), which is designed to determine the percentage of platelet aggregation in fresh whole blood samples taken during interventional cardiac procedures. It measures the change in the platelet count due to the aggregation of functional platelets in the blood sample. This is the first bedside test to simultaneously measure both platelet count and platelet aggregation.

An experimental device, a dynamic clot retractometer (Hemodyne), measures platelet force development by exerting a tensile force on a platelet clot. (47) The device is based on the principle of clot retraction and measures both the tensile properties of the platelet cytoskeleton cytoskeleton

System of microscopic filaments or fibres, present in the cytoplasm of eukaryotic cells (see eukaryote), that organizes other cell components, maintains cell shape, and is responsible for cell locomotion and for movement of the organelles within it.
 and the integrity of the glycoprotein IIb/IIa receptor--fibrinogen linkage. Decreased platelet force development has been detected with this device in uremia uremia (yrē`mēə), condition resulting from advanced stages of kidney failure in which urea and other nitrogen-containing wastes are found in the blood.  and with glycoprotein IIb/IIIa antagonists, (48) and increased force development has been detected in patients with coronary artery disease coronary artery disease, condition that results when the coronary arteries are narrowed or occluded, most commonly by atherosclerotic deposits of fibrous and fatty tissue. .

Flow cytometry has been used to study platelet structure and function, but this technique is used only in specialized centers. Flow cytometric analysis is based on the detection of cell surface proteins with fluorescently labeled antibodies. It has been used in the detection of platelet activation by using antibodies to proteins newly expressed on the platelet surface during activation, such as P-selectin or thrombospondin, or by detecting new epitopes on glycoprotein IIb/IIIa induced by binding fibrinogen (ligand-induced binding sites). (49) Flow cytometric evaluation of P-selectin (CD62P) expression has been used to distinguish heparin-induced thrombocytopenia (HIT) from HIT with thrombosis, which may allow for early intervention for prevention-of thrombotic complications. (50) Flow cytometry, using fluorescently labeled abciximab, can be used to determine the number of inhibited glycoprotein IIb/IIIa receptors after the infusion of glycoprotein Ib/IIIa inhibitors. (51) It can also measure platelet activation, which may correlate with thrombotic risk in certain clinical situations. (52) Platelet flow cytometry can be used to diagnose deficiencies of platelet surface glycoproteins. It has been used to detect the absence of glycoprotein IIb/IIIa receptors in patients with Glanzmann thrombasthenia and has been used to study deficiencies of glycoprotein Ia, Ib, IIb, IV, and IX. (53) Flow cytometric methods have also been used to measure dense granules (mepacrine mepacrine

see quinacrine.
 uptake or release), aggregation, microparticle formation, and platelet procoagulant activity. (54)

Another use of flow cytometry is the detection of platelet autoantibodies in patients with idiopathic thrombocytopenic purpura Idiopathic Thrombocytopenic Purpura Definition

Idiopathic thrombocytopenic purpura, or ITP, is a bleeding disorder caused by an abnormally low level of platelets in the patient's blood.
 and drug-induced thrombocytopenias, which is sensitive but not specific. (55) This test can be made more specific for drug-induced antibodies by incubating the platelets in the presence of the drugs in question or by using activation-dependent tests, such as [sup.51]Cr release (56) or [sup.14]C serotonin release. (57) Antigen capture assays, such as monoclonal antibody immobilization Immobilization Definition

Immobilization refers to the process of holding a joint or bone in place with a splint, cast, or brace. This is done to prevent an injured area from moving while it heals.
 of platelet antigens (MAIPA MAIPA Monoclonal Antibody Immobilization of Platelet Antigen
MAIPA Motorola ASCII International Phonetic Alphabet
), have improved specificity further by being able to detect antibody binding to specific platelet surface glycoproteins. (58)

Platelets with increased RNA RNA: see nucleic acid.
RNA
 in full ribonucleic acid

One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic
 content (reticulated platelets) can be measured by flow cytometry using the dye thiazole thi·a·zole  
n.
1. A colorless or pale yellow liquid, C3H3NS, containing a five-member ring composed of a nitrogen atom, a sulfur atom, and three carbon atoms, used in making dyes and fungicides.

2.
 orange, which binds to RNA and DNA DNA: see nucleic acid.
DNA
 or deoxyribonucleic acid

One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes.
. (23,59) This technique is gaining acceptance as a diagnostic tool to evaluate whether thrombocytopenia is due to increased platelet destruction or decreased platelet production, since platelets newly released from bone marrow have increased RNA content. This assay has recently been automated on the Cell Dyn instruments (Abbott, Abbott Park, III). It is anticipated that implementation of reticulated platelet counts may help to avoid bone marrow examination in some individuals with thrombocytopenia.

Electron microscopy may be used for the ultrastructural evaluation of platelets, particularly in patients with suspected SPDs, showing a decrease or absence of the organelles (cytoplasmic dense granules) that store adenine nucleotides, serotonin, and calcium. (28) Giant platelet disorders also have characteristic electron microscopic findings. (28,60) Other specialized methods of platelet evaluation, such as crossed immunoelectrophoresis Immunoelectrophoresis

A combination of the techniques of electrophoresis and immunodiffusion used to separate the components of a mixture of antigens and make them visible by reaction with specific antibodies.
, will be discussed in the following section with the individual disorders for which they are useful.

DIAGNOSTIC CATEGORIES OF PLATELET-DERIVED BLEEDING DIATHESIS

Platelet disorders may be divided into 3 major categories: platelet dysfunction associated with normal, decreased, or increased platelet counts, as shown in the algorithms in Figures 2, 3, and 5. In all of the disorders discussed herein, the results of the coagulation screening tests PT and APTT should be considered normal.

[FIGURES 2-3 and 5 OMITTED]

Platelet Dysfunction With Normal Platelet Count

Platelet dysfunction with a normal platelet count usually indicates a qualitative platelet disorder. In following the algorithm in Figure 2, these disorders would be evaluated in a patient with a normal PT, APTT, and platelet count. The results of a platelet function screening test would be abnormal and test results for von Willebrand disease would be normal. Platelet aggregation studies would then be used to distinguish the following disorders, followed by more specific tests, if required. Most drug-induced platelet dysfunction will also demonstrate platelet dysfunction with a normal platelet count, so it is extremely important to take a careful drug history. (16) A list of drugs that cause platelet dysfunction can be found in Table 1. Platelet aggregation abnormalities typically found with drugs such as aspirin, glycoprotein IIb/IIIa antagonists, or the thienopyridines can be found in Table 2.

Glanzmann thrombasthenia is a congenital deficiency or dysfunction of glycoprotein IIb/IIIa, the receptor for fibrinogen responsible for mediating platelet aggregation. (61,62) It is an autosomal recessive disorder that manifests in lifelong mucocutaneous bleeding. Glanzmann thrombasthenia can be classified according to the amount of glycoprotein IIb/IIIa: type I, 0% to 5% of normal; type II, 6% to 20% of normal; and variant disease, 50% to 100% of normal with abnormal fibrinogen binding. (63) Mutations of both glycoprotein IIb and glycoprotein IIIa have been implicated. (63) In patients with Glanzmann thrombasthenia, the bleeding time or platelet function screening test results will be abnormal. No aggregation response will be seen on addition of ADP, collagen, epinephrine, and arachidonic acid-aggregating agents, whereas the ristocetin-induced aggregation is normal. (40) This finding is virtually diagnostic of Glanzmann thrombasthenia, but the disorder can be confirmed by platelet flow cytometry or crossed immunoelectrophoresis of platelet membrane proteins (Table 2). (64) Afibrinogenemia, a rare deficiency of fibrinogen, can present with similar initial platelet aggregation results, but the aggregation defect in afibrinogenemia is restored with addition of fibrinogen to the specimen. Additional laboratory studies in patients with Glanzmann thrombasthenia will show decreased platelet-associated fibrinogen, defective fibrinogen binding to platelets, and decreased clot retraction. (65)

Bernard-Soulier disease is a congenital deficiency of the platelet glycoprotein Ib[alpha]/Ib[beta]/IX/V receptor, the surface receptor for VWF-mediated platelet aggregation. (66) The disorder is inherited as an incompletely recessive recessive /re·ces·sive/ (re-ses´iv)
1. tending to recede; in genetics, incapable of expression unless the responsible allele is carried by both members of a pair of homologous chromosomes.

2.
 autosomal Autosomal
Relating to any chromosome besides the X and Y sex chromosomes. Human cells contain 22 pairs of autosomes and one pair of sex chromosomes.

Mentioned in: Ataxia-Telangiectasia, Cutis Laxa, Hemochromatosis
 trait with severe bleeding. Many patients with Bernard-Soulier disease have moderately severe thrombocytopenia with large platelets, and this disorder is included with the macrothrombocytopenia syndromes discussed herein. Most of the Bernard-Soulier genetic defects are due to mutations of the GPIb[alpha] gene, but may also be due to defects of the GPIb[beta] or GPIX genes. (67,68) Glycoprotein Ib is expressed on the demarcation membrane system in the megakaryocytes that is responsible for platelet fragmentation, so it is postulated that glycoprotein Ib plays a role during megakaryopoiesis and maintenance of platelet size. (17) Normal platelet aggregation is noted with exposure to ADP, collagen, epinephrine, and arachidonic acid, but aggregation is absent with the addition of ristocetin. (65) Adhesion of platelets to subendothelium or immobilized VWF is markedly reduced at all shear rates in patients with Bernard-Soulier syndrome; this finding may have direct clinical consequences. (69) The glycoprotein abnormality can be confirmed with flow cytometry or crossed immunoelectrophoresis. (70) Additional laboratory studies show normal VWF antigen and ristocetin cofactor activity to distinguish Bernard-Soulier syndrome from von Willebrand disease.

Abnormalities of platelet secretion can be due to either deficiency of platelet granules or defects in the signal transduction events that regulate secretion or aggregation. (71) Platelet SPDs can be congenital or acquired and are the result of either a deficiency of granules (alpha and/or dense granules) or defective granule release on platelet activation. (72) Dense granule SPDs ([delta]-SPDs) can be seen as a singular clinical entity or as part of other hereditary disorders, such as Chediak-Higashi, Hermansky-Pudlak syndrome, thrombocytopenia-absent radius syndrome thrombocytopenia-absent radius syndrome
n.
Congenital absence of the radius accompanied by thrombocytopenia and sometimes by congenital heart disease and renal anomalies. Also called TAR syndrome.
, or Wiskott-Aldrich syndrome. (72-74) Often [delta]-SPD shows decreased aggregation response to ADP, epinephrine, and collagen with normal aggregation to arachidonic acid and ristocetin. Decreased adenosine triphosphate release by lumiaggregometry and decreased mepacrine uptake or release by flow cytometry are observed. Ultrastructural abnormalities in these disorders usually show decreased dense granules. In addition, [alpha]-SPD (Gray platelet syndrome) has decreased alpha granules and is usually considered a macrothrombocytopenia. (75) A rare [alpha]/[delta]-SPD has been described that has features of both disorders. (72) Acquired platelet storage pool disorders can be seen with underlying myeloproliferative disorders in which the platelet degranulation is defective as a result of the disease. Circulating "exhausted" platelets simulating SPDs can be observed in clinical scenarios where there is ongoing in vivo platelet activation, such as cardiopulmonary bypass, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura thrombotic thrombocytopenic purpura
n.
A disease of unknown origin, characterized by abnormally low levels of platelets in the blood, the formation of blood clots in the arterioles and capillaries of many organs, and neurological damage.
 or hemolytic uremic syndrome hemolytic uremic syndrome
n.
A syndrome in which hemolytic anemia and thrombocytopenia occur with acute renal failure, marked in children by sudden gastrointestinal bleeding, urine that contains red blood cells and is scanty in volume, and
.

In addition to the SPDs, platelet release defects can be seen with defects of platelet signal transduction. In general, these disorders are poorly defined, but may constitute a significant percentage of patients with abnormal secondary wave of aggregation and decreased granule release, in whom alpha and dense granules are not deficient. (71) Defects of the platelet receptors for thromboxane thromboxane /throm·box·ane/ (-bok´san) either of two compounds, one designated A2 and the other B2. Thromboxane A2 is synthesized by platelets and is an inducer of platelet aggregation and platelet release functions and is a  A2, collagen, ADP, and epinephrine are included in this category. (76-78) Defects of the collagen and epinephrine receptors can be distinguished because usually they demonstrate a selective defect in aggregation to a single agonist. (76,77) These disorders can be confirmed by flow cytometry, where a deficiency of a surface glycoprotein is identified. Defects of the signaling pathways, including G protein activation, phospholipase C activation, calcium mobilization, pleckstrin phosphorylation phosphorylation, chemical process in which a phosphate group is added to an organic molecule. In living cells phosphorylation is associated with respiration, which takes place in the cell's mitochondria, and photosynthesis, which takes place in the chloroplasts. , and tyrosine phosphorylation, have also been described. (71) In general, these patients show decreased primary aggregation and decreased granule release without granule deficiency. Identification of the exact defect requires detailed biochemical studies, which are not available in most laboratories. Defects of thromboxane A2 synthesis have been described, including defective liberation of arachidonic acid from the platelet membrane, cyclooxygenase enzyme deficiency, or thromboxane synthase synthase /syn·thase/ (-thas) a term used in the names of some enzymes, particularly lyases, when the synthetic aspect of the reaction is dominant or emphasized.

syn·thase
n.
 deficiency. (79) These individuals will display an aspirin-like defect in aggregation despite having never used aspirin therapy.

Platelets play an important procoagulant role with assembly of coagulation complexes on activated platelet membranes that are rich in phosphatidyl serine. A rare congenital platelet functional disorder is Scott syndrome, due to defective "flip" of phosphatidyl serine to the outer table of the platelet membrane. (80) These patients will have normal platelet aggregation studies, but have abnormal platelet procoagulant activity (platelet factor 3) and microparticle formation.

Other significant disorders of platelet function with platelet counts in the normal range are usually acquired with the presence of another disease or drug therapy. These are, by far, more common than the disorders described herein. Platelet dysfunction is often observed with chronic renal failure chronic renal failure Chronic kidney failure Nephrology A slow decline in renal function, which may be 2º to chronic HTN, DM, CHF, SLE, or sickle cell anemia and, if extreme, leads to ESRD, mandating kidney dialysis; an abrupt decline in renal function may be  or liver disease, in patients experiencing a variety of myeloproliferative myeloproliferative /my·elo·pro·lif·er·a·tive/ (-pro-lif´er-ah-tiv) pertaining to or characterized by medullary and extramedullary proliferation of bone marrow constituents; see under disorder.  and lymphoproliferative disorders (ie, polycythemia vera, myelofibrosis Myelofibrosis Definition

Myelofibrosis is a rare disease of the bone marrow in which collagen builds up fibrous scar tissue inside the marrow cavity.
, paroxysmal nocturnal hemoglobinuria paroxysmal nocturnal hemoglobinuria
n.
An infrequent disorder the onset of which usually occurs in the third or fourth decades of life and is characterized by periods of hemolytic anemia, hemoglobinuria primarily at night, pallor, bronzing of the skin,
, acute myelogenous leukemia acute myelogenous leukemia
n. Abbr. AML
Myelogenous leukemia characterized by rapid abnormal increase in the number of myeloblasts and progression of symptoms.
, and hairy cell leukemia Hairy Cell Leukemia Definition

Hairy cell leukemia is a disease in which a type of white blood cell called the lymphocyte, present in the blood and bone marrow, becomes malignant and proliferates.
). Platelet dysfunction also may be associated with a variety of clinical scenarios, such as previous cardiopulmonary bypass, implantation of prosthetic pros·thet·ic
adj.
1. Serving as or relating to a prosthesis.

2. Of or relating to prosthetics.



prosthetic

serving as a substitute; pertaining to prostheses or to prosthetics.
 materials such as vascular grafts and prosthetic heart valves, and ventricular assistance devices. (81, 82) Platelet dysfunction in these disorders is usually difficult to characterize because nonspecific nonspecific /non·spe·cif·ic/ (non?spi-sif´ik)
1. not due to any single known cause.

2. not directed against a particular agent, but rather having a general effect.


nonspecific

1.
 defects of platelet aggregation are usually observed.

Platelet Disorders With Thrombocytosis

Patients with elevated platelet counts may have clinical bleeding, but may also be asymptomatic or have thrombosis. In these patients, laboratory evaluation should be primarily aimed at elucidating the cause of the thrombocytosis and should include a complete blood cell count, peripheral blood smear, bone marrow evaluation, cytogenetic cytogenetic /cy·to·ge·net·ic/ (-je-net´ik)
1. pertaining to chromosomes.

2. pertaining to cytogenetics.


cytogenetic

pertaining to or originating from the origin and development of the cell.
 study, and platelet aggregation study. In general, platelet function screening tests have little usefulness in evaluating these disorders and do not necessarily correlate with further platelet function tests. In patients with thrombocytosis, the differential diagnosis is primarily between a reactive thrombocytosis and a myeloproliferative process (essential thrombocytosis, chronic myelogenous leukemia Chronic myelogenous leukemia (CML)
Also called chronic myelocytic leukemia, malignant disorder that involves abnormal accumulation of white cells in the marrow and bloodstream.

Mentioned in: Bone Marrow Transplantation
, polycythemia vera, and myelofibrosis). The algorithmic approach to the diagnosis of thrombocytosis is shown in Figure 2. In general, patients with a myeloproliferative disorder often have platelet counts greater than 1 X [10.sup.6]/[micro]L, and patients with reactive thrombocytoses have counts less than this, but there is a great deal of overlap. For myeloproliferative disorders, characteristic features of a specific disease can be discerned by examination of the peripheral blood smear, bone marrow, and cytogenetic studies.

Platelet aggregation studies alone can suggest an underlying myeloproliferative disorder, particularly when epinephrine-induced aggregation alone is reduced or absent. (83,84) The decreased epinephrine-induced aggregation is thought to be due to down-regulation of [[alpha].sub.2]-adrenergic receptors. (83) This pattern of platelet aggregation is also observed in patients with a congenital defect of the [[alpha].sub.2]-adrenergic receptors, (76) but these patients usually have a normal platelet count. Other patterns of platelet dysfunction with myeloproliferative disorders include decreased platelet aggregation to ADP or collagen, dense-granule storage pool pattern, abnormal platelet morphologic structure, abnormalities of the arachidonic acid pathway, and decreased receptors for prostaglandin [D.sub.2]. (83,85) Additionally, some patients may show increased aggregation with various agonists or may have spontaneous aggregation without added agonists. (86) In the clinical evaluation of patients with myeloproliferative disorders, both bleeding and thrombosis can be observed in these patients, and the results of the platelet functional tests will not necessarily distinguish whether the patient is at risk for bleeding or thrombosis. (87)

In contrast to patients with myeloproliferative disorders, patients with reactive thrombocytosis usually have normal platelet function. A reactive, or secondary, thrombocytosis can be associated with many clinical entities, such as iron deficiency, inflammatory and infectious disorders after splenectomy Splenectomy Definition

Splenectomy is the surgical removal of the spleen, which is an organ that is part of the lymphatic system. The spleen is a dark-purple, bean-shaped organ located in the upper left side of the abdomen, just behind the bottom of the
 in malignancies such as carcinomas or lymphomas, myelodysplastic disorders, smoking, or exercise. It can also be observed as a rebound thrombocytosis following splenectomy, treatment for idiopathic thrombocytopenic purpura, pernicious anemia, or cessation of myelosuppressive drugs.

Platelet Disorders With Thrombocytopenia

Disorders in which the platelet count is decreased can be divided, for evaluation purposes, by the size of the platelets. Thrombocytopenias can be congenital or acquired, but they have been grouped by platelet size in- this discussion. See Figure 3 for an algorithmic approach to small and large platelets and Figure 5 for an approach to the diagnosis of normal-sized platelets.

Thrombocytopenia with small platelets can be seen in patients with Wiskott-Aldrich syndrome. This is an X-linked recessive disorder characterized by recurrent infections, eczema, and thrombocytopenia. These individuals will have absent immunologic responses to polysaccharide polysaccharide: see carbohydrate.
polysaccharide

Any of a large class of long-chain sugars composed of monosaccharides. Because the chains may be unbranched or branched and the monosaccharides may be of one, two, or occasionally more kinds,
 antigens and progressive decline in T-lymphocyte function. The MPV is often low (approximately half the normal size) and lymphocytes are deficient in CD43 (sialophorin). (88) Platelet dysfunction is severe; the platelets are unable to aggregate and a storage pool-like pattern is often seen. (89) Patients with thrombocytopenia due to marrow aplasia aplasia /apla·sia/ (ah-pla´zhah) lack of development of an organ or tissue.aplas´tic

aplasia axia´lis extracortica´lis conge´nita  familial centrolobar sclerosis.
 may also have small platelets, but the MPV is usually low to normal not decreased.

The rare macrothrombocytopenia disorders are all congenital in nature and most are inherited in an autosomal dominant fashion. They are usually due to congenital defects in platelet production by megakaryocyte megakaryocyte /mega·karyo·cyte/ (-sit?) the giant cell of bone marrow containing a greatly lobulated nucleus, from which mature blood platelets originate.megakaryocyt´ic

meg·a·kar·y·o·cyte
n.
 or demarcation membrane systems, although the structural or genetic abnormalities are known in only a few disorders (Figure 3). (17) Some patients with acquired platelet destruction and turnover, such as idiopathic thrombocytopenic purpura, may have high MPVs due to the rapid release of new platelets, but, in general, the macrothrombocytopenia syndrome platelets are much larger and more uniform in size.

Several macrothrombocytopenia disorders are characterized by the presence of neutrophilic neutrophilic /neu·tro·phil·ic/ (-fil´ik)
1. pertaining to neutrophils.

2. stainable by neutral dyes.


neutrophilic

1. pertaining to neutrophils.

2. stainable by neutral dyes.
 inclusions. May-Hegglin anomaly is the most common macrothrombocytopenia and is an autosomal dominant disorder Noun 1. autosomal dominant disorder - a disease caused by a dominant mutant gene on an autosome
autosomal dominant disease

congenital disease, genetic abnormality, genetic defect, genetic disease, genetic disorder, hereditary condition, hereditary disease,
 characterized by Dohle body inclusions in neutrophils with a mild bleeding disorder. (17,90) The Dohle bodies are blue, spindle-shaped inclusions in the periphery of the neutrophil neutrophil /neu·tro·phil/ (noo´tro-fil)
1. a granular leukocyte having a nucleus with three to five lobes connected by threads of chromatin, and cytoplasm containing very fine granules; cf. heterophil.

2.
 cytoplasm (Figure 4). The thrombocytopenia is usually moderate, with platelet counts of 60 to 100 X [10.sup.3]/[micro]L, and the mean MPV is approximately 12.5 fL, but is often much larger. Laboratory studies will usually show normal platelet aggregation and a normal bleeding time, (91) attesting to the increased functionality of the larger platelets. Electron microscopic analysis of platelets in the May-Hegglin anomaly will often show a disorganization disorganization /dis·or·gan·iza·tion/ (-or?gan-i-za´shun) the process of destruction of any organic tissue; any profound change in the tissues of an organ or structure which causes the loss of most or all of its proper characters.  of the microtubules Microtubules
Slender, elongated anatomical channels in worms.

Mentioned in: Antihelminthic Drugs
. (17,91) Electron microscopic analysis of the neutrophilic inclusions shows them to lack a limiting membrane, be free of specific granules, and contain parallel bundles of ribosomes Ribosomes

Small particles, present in large numbers in every living cell, whose function is to convert stored genetic information into protein molecules.
, microfilaments microfilaments,
n.pl any of the submicroscopic cellular filaments, such as the tonofibrils, found in the cytoplasm of most cells, that function primarily as a supportive system.
, and segments of endoplasmic endoplasmic

pertaining to or arising from endoplasm.


endoplasmic ribosomes
small, cytoplasmic granules consisting of approximately 60% RNA and 40% protein.
 reticulum reticulum /re·tic·u·lum/ (re-tik´u-lum) pl. retic´ula   [L.]
1. a small network, especially a protoplasmic network in cells.

2. reticular tissue.
. (17) Platelet surface glycoproteins are usually normal. (92)

[FIGURE 4 OMITTED]

The 2 other macrothrombocytopenia disorders with neutrophilic inclusion are Fechtner syndrome and Sebastian syndrome. Fechtner syndrome can be distinguished by hereditary nephritis, deafness, cataracts (Alport syndrome), and macrothrombocytopenia with a mild-to-moderate bleeding disorder. (60) The MPV may be as large as 20 fL, and the peripheral smear shows uniformly giant platelets with pale blue, irregularly shaped inclusions in the neutrophil cytoplasm. (17) Platelet aggregation studies and platelet surface glycoprotein studies are normal. Sebastian syndrome (93) has no clinical associations like Fechtner syndrome.

There are several rare macrothrombocytopenia syndromes without neutrophil inclusions, which are generally characterized by either surface glycoprotein abnormalities or platelet functional defects. Bernard-Soulier syndrome lacks glycoprotein Ib/IX/V on platelet surfaces, as has been discussed herein. Patients who are heterozygous het·er·o·zy·gous
adj.
1. Having different alleles at one or more corresponding chromosomal loci.

2. Of or relating to a heterozygote.
 for the disease will show only giant platelets on the blood smear without hypoplatelet function, thrombocytopenia, or bleeding. These heterozygous patients may have associated velopharyngeal insufficiency, conotruncal heart disease, and learning disabilities together with an abnormality of glycoprotein Ib[beta], and are classified as having the velocardiofacial syndrome. (94) The Gray platelet syndrome is an autosomal dominant [alpha]-SPD characterized by mild bleeding symptoms, reticulin reticulin /re·tic·u·lin/ (re-tik´u-lin) a scleroprotein from the connective fibers of reticular tissue.

re·tic·u·lin
n.
 fibrosis of the bone marrow, variable thrombocytopenia, and large (mean, 13 fL), gray-appearing platelets on the peripheral blood smear due to decreased alpha granules. (75) Pale platelets can also be seen with ongoing platelet activation and circulating "exhausted" platelets, but in these patients there will be a mixture of normal and pale platelets. It is unclear whether the pathophysiologic origin of the Gray platelet syndrome is due to premature release of alpha granules from the cell or abnormal signal transduction or calcium flux. (17) Platelet aggregation study results may be abnormal for thrombin and collagen, and flow cytometry studies have shown increased surface P-selectin, but decreased alpha granule P-selectin. (75) Other rare macrothrombocytopenias are listed in Figure 3. Those that have known surface glycoprotein abnormalities include the glycoprotein IV abnormality and mitral valve insufficiency Mitral Valve Insufficiency Definition

Mitral valve insufficiency is a term used when the valve between the upper left chamber of the heart (atrium) and the lower left chamber (ventricle) does not close well enough to prevent back flow of blood when the
 with abnormalities of glycoproteins Ia, Ic, and IIa. (17)

Bone marrow examination may be helpful in differentiating the underlying causes in thrombocytopenic platelet disorders with normal platelet morphologic structure and size. This group of disorders includes both congenital and acquired thrombocytopenias that are usually due to either decreased platelet production or increased platelet destruction (Figure 5). The number of megakaryocytes on the bone marrow can help to distinguish between these origins, but analysis of platelet turnover by messenger RNA analysis may also be helpful.

The finding of adequate or increased megakaryocytes on the bone marrow or increased reticulated platelets suggests peripheral platelet destruction. Platelet functional tests are usually not helpful in differentiating between the entities in this class of disorders, since most functional studies will give abnormal results simply because of the low platelet number. The overall MPV is usually normal with destructive thrombocytopenia, but there is usually a range of platelet size and many large platelets are seen, indicating the rapid platelet turnover. These disorders are invariably in·var·i·a·ble  
adj.
Not changing or subject to change; constant.



in·vari·a·bil
 acquired and an underlying abnormality should be sought. In general, the clinical scenario is the most helpful in classifying these disorders.

Idiopathic thrombocytopenic purpura is known to be due to platelet sensitization sensitization /sen·si·ti·za·tion/ (sen?si-ti-za´shun)
1. administration of an antigen to induce a primary immune response.

2. exposure to allergen that results in the development of hypersensitivity.
, with autoantibodies leading to platelet destruction in the reticuloendothelial system; peripheral smears may show variable macrothrombocytopenia and autoantibodies to specific surface glycoproteins can be detected by flow cytometry or immunoassay, (95) although diagnosis is largely from clinical findings. Another immune thrombocytopenia is posttransfusion purpura, where immune destruction of both transfused and recipient platelets is seen, usually beginning 5 to 12 days after transfusion. Patients often have abnormal platelet antigens and are frequently [PL.sup.A1] negative ([PL.sup.A2] homozygous ho·mo·zy·gous
adj.
Having the same alleles at one or more gene loci on homologous chromosome segments.


Homozygous
Identical genes controlling a specified inherited trait.
 or HPA-1b). (96) Anti-[PL.sup.A1] antibodies can be detected both in plasma and attached to the platelet surface. Neonatal alloimmune thrombocytopenia neonatal alloimmune thrombocytopenia Fetal alloimmune thrombocytopenia, see there  occurs when the mother lacks a platelet antigen present on the neonates platelets. Maternal antibodies cross the placenta and cause severe thrombocytopenia shortly after birth. Several platelet antigen systems may be responsible for this scenario, but often the mother is [PA.sup.A1] negative ([PL.sup.A2] homozygote homozygote (hō'mōzī`gōt): see genetics. ). (97) Interestingly, this same [PL.sup.A2] genetic polymorphism may impart a risk for coronary artery disease. (98)

The thrombocytopenia of thrombotic thrombocytopenic purpura is thought to be secondary to deficiency of a VWF-cleaving metalloproteinase in many patients, leading to diffuse thrombus thrombus /throm·bus/ (throm´bus) pl. throm´bi   a stationary blood clot along the wall of a blood vessel, frequently causing vascular obstruction.  formation in small vessels and a decline of circulating platelets. (99) These patients will show characteristic clinical symptoms with renal failure, mental status changes, fever, and hemolysis hemolysis (hĭmŏl`ĭsĭs), destruction of red blood cells in the bloodstream. Although new red blood cells, or erythrocytes, are continuously created and old ones destroyed, an excessive rate of destruction sometimes occurs.  with prominent schistocytes on the peripheral blood smear, but normal screening coagulation test results. (100) Thrombotic thrombocytopenic purpura has also been associated with Shiga toxin-producing strains of Escherichia coli and with drugs such as cyclosporine cyclosporine /cy·clo·spor·ine/ (-spor´en) a cyclic peptide from an extract of soil fungi that selectively inhibits T cell function; used as an immunosuppressant to prevent rejection in organ transplant recipients and to treat severe , quinine quinine (kwī`nīn', kwĭnēn`), white crystalline alkaloid with a bitter taste. Before the development of more effective synthetic drugs such as quinacrine, chloroquine, and primaquine, quinine was the specific agent in the treatment of , ticlopidine, and clopidogrel. (100-103) An assay for the VWF-cleaving metalloproteinase is now available, but because it is based on the VWF-multimer assay, is not readily available in most laboratories. (99)

Drug-induced thrombocytopenias due to immunologic platelet destruction can be seen with many drugs, but the most common offenders are quinidine quinidine (kwĭn`ĭdēn'), heart muscle relaxant used to maintain regular heart rhythm patterns. It is an alkaloid chemically similar to quinine and, like quinine, occurs naturally in some species of cinchona trees. , quinine, heparin, sulfonamide drugs, and gold salts. (104) This syndrome has also been described with the glycoprotein IIb/IIIa antagonist abciximab, but because this drug is based on a monoclonal antibody to the fibrinogen receptor (Fab' fragment), the thrombocytopenia may not be alloimmune in origin. (105) Drug-induced thrombocytopenias can be diagnosed by detecting the presence of platelet-associated antibody by flow cytometry, although this is a nonspecific finding that can also be seen with infections and autoimmune disorders. The drug dependence of the antibody binding can be demonstrated by incubating platelets with patient plasma in the presence of the drug. (55)

Heparin-induced thrombocytopenia is a distinctive drug-induced thrombocytopenia associated with heparin therapy, where antibodies are formed to heparin-platelet factor 4 complexes, leading to platelet aggregation, platelet microparticle formation, endothelial injury, and paradoxical thrombosis. (106) The thrombotic complications can be either venous or arterial and may cause death, limb loss, and pulmonary thrombosis. Bleeding secondary to thrombocytopenia is rare in HIT. The thrombocytopenia is often delayed 5 to 12 days after starting heparin therapy and usually resolves after heparin therapy is stopped. Specific laboratory tests, such as heparin-induced platelet aggregation, serotonin release, and heparin-platelet factor 4 enzyme-linked immunosorbent assay enzyme-linked immunosorbent assay
n.
ELISA.


Enzyme-linked immunosorbent assay (ELISA)
A diagnostic blood test used to screen patients for AIDS or other viruses.
, are available to positively diagnose this disorder. (106,107)

Thrombocytopenias due to decreased platelet production include both rare congenital and more common acquired causes (Figure 3). Congenital thrombocytopenias due to decreased megakaryocytes with normal platelet size include thrombocytopenia-absent radius syndrome, X-linked megakaryocytic thrombocytopenia, and Fanconi anemia. This last disorder is distinguished by erythroid erythroid /er·y·throid/ (er´i-throid)
1. of a red color; reddish.

2. pertaining to the cells of the erythrocytic series.


er·y·throid
adj.
1.
 hypoplasia hypoplasia /hy·po·pla·sia/ (-pla´zhah) incomplete development or underdevelopment of an organ or tissue.hypoplas´tic

enamel hypoplasia
 and DNA instability. Acquired megakaryocytic hypoplasia is seen with myelophthisic disorders, viral illnesses, and drug-induced hypoplasia. (104)

ACTIVATED PLATELET SYNDROMES

Some patients with myeloproliferative disorders will show evidence of activated platelets or hyperplatelet function. Although most patients with essential thrombocythemia and polycythemia vera will display hypoaggregation, some will actually show an increased response to various agonists, excluding epinephrine. (85) Some of these patients will also exhibit spontaneous platelet aggregation in vitro. In vitro hypoplatelet or hyperplatelet function in patients with myeloproliferative disorders does not necessarily correlate with clinical symptoms of bleeding or thrombosis.

The sticky platelet syndrome is a poorly defined disorder associated with arterial and venous thromboembolic thromboembolic

pertaining to or emanating from thromboembolism.


thromboembolic meningoencephalitis
see hemophilosis.

thromboembolic parasitism
see thromboembolic colic.
 events characterized by hyperaggregability of platelets on exposure to ADP and epinephrine. The molecular mechanism of this disorder is not known, but it has been suggested that emotional stress may be a precipitating factor for systemic thrombosis. (108)

Platelet activation is known to occur in patients with concomitant cardiovascular disease, (109) hypertension, (110) and diabetes, (111) most likely due to platelet activation secondary to vascular injury. Additionally, abnormal glycation is thought to contribute to abnormalities of platelet function in diabetic patients. (112) Older patients with hypertension are found to have a higher prevalence of thromboembolic tendencies-associated with platelet hyperactivity. (113) Genetic polymorphisms of the glycoprotein IIIa platelet membrane receptor gene (the [Pl.sup.A2] genotype) may predispose patients with this allele allele (əlēl`): see genetics.
allele

Any one of two or more alternative forms of a gene that may occur alternatively at a given site on a chromosome.
 to a higher risk of acute coronary and cerebrovascular cer·e·bro·vas·cu·lar
adj.
Relating to the blood supply to the brain, particularly with reference to pathological changes.



cerebrovascular

pertaining to the blood vessels of the cerebrum or brain.
 events, although the mechanism for the thrombotic tendency is uncertain. (98) Additional genetic polymorphisms of other platelet surface proteins are being investigated as risk factors for cardiovascular disease.

Various techniques for the diagnosis of in vivo platelet activation or increased platelet function are available. Spontaneous in vitro platelet aggregation or the finding of increased aggregation response to low concentrations of platelet agonists suggests increased platelet function. The detection of circulating platelet aggregates may be made either by flow cytometry or by collecting a whole blood sample into a fixative fixative /fix·a·tive/ (fik´sit-iv) an agent used in preserving a histological or pathological specimen so as to maintain the normal structure of its constituent elements.

fix·a·tive
adj.
. (114) Platelet flow cytometry can also be used to detect circulating activated platelets due to neoexpression of new surfaces markers (ie, P-selectin or CD63) or by detecting proteins bound to platelet surface glycoproteins (ie, fibrinogen, thrombospondin). (49,52) Some caution must be exercised in the diagnosis of increased platelet activation, because persistent in vivo activation can lead to degranulation of platelets with the detection of hypoaggregation in the laboratory.

CONCLUSION

Multiple causes exist for platelet-derived bleeding diatheses. The laboratory evaluation of these disorders can range from simple to complex as outlined herein, but should initially include a thorough evaluation of the patient's medical history, concentrating on personal and familial bleeding disorders and all current medications. With this as a starting point, the clinician and/or pathologist may find algorithms such as those presented herein helpful to guide investigation toward elucidating the underlying origin for platelet-derived bleeding.
Table 1. Drugs That Affect Platelet Function *

Nonsteroidal anti-inflammatory      Psychotropics and anesthetics
  drugs (NSAIDs)                     Tricyclic antidepressants
 Aspirin                              (ie, imipramine)
 Ibuprofen                           Phenothiazines (ie,
 Mefenamic acid                       chlorpromazine)
 Indomethacin                        Local and general anasthesia
 Cox-2 inhibitors                     (ie, halothane)

Antimicrobials                      Chemotherapeutic agents
 Penicillins                         Mithramycin
 Cephalosporin                       Daunorubicin
 Nitrofurantoin                      Carmustine
 Hydroxychloroquine
 Amphotericin                       Miscellaneous agents
                                     Dextrans
Cardiovascular agents                Radiographic contrast
 [beta]-Adrenergic blockers          Quinidine
  (ie, propanol)                     Ethanol
 Vasodilators (ie, nitropursside,
  nitroglycerin)                    Foods
 Diuretics (ie, furosemide)          Caffeine
 Calcium channel blockers            Garlic
                                     Cumin
Anticoagulants                       Turmeric
 Heparin
 Coumadin                           Antiplatelet drugs
 Lepirudin                           Phosphodiesterase inhibitors
 Argatroban                           Dipyridamole
 Bivalirudin                          Cilostazole

Thrombolytic agents                 Adenosine diphosphate receptor
 Streptokinase                       antagonists
 Urokinase                            Ticlopidine
 Tissue plasminogen activator         Clopidogrel

                                    Glycoprotein IIb/IIIA antagonists
                                      Abciximab
                                      Eptifibatide
                                      Tirofiban

* Adapted from George and Shattil. (16)
Table 2. Aggregation Characteristics *

                                      ADP

        Disorder            Primary       Secondary          AA

VWD                       N              N              N

Glanzmann throm-          [down arrow]   [down arrow]   [down arrow]
 basthenia                 or Abs         or Abs         or Abs
Bernard-soulier syn-      N              N              N
 drome
Dense granule plate-      N              [down arrow]   N
 let storage pool
 disorder ([delta]-SPD)
[alpha]-SPD               Var            Var            N
Signal transduction       N              [down arrow]   Var [down
 disorders                                               arrow]
Aspirin-like drug or      N              [down arrow]   [down arrow]
 defects of throm-                       [down arrow]    or Abs
 boxane synthesis
Myeloproliferative        N              N              N
 disorder
Scott syndrome            N              N              N
Uremia                    N              [down arrow]   [down arrow]
Thienopyridines (ti-      [down arrow]   Abs            N
 clopidine and clo-
 pidogrel)
GP IIb/IIIa antago-       [down arrow]   [down arrow]   [down arrow]
 nists                     or Abs         or Abs         or Abs

        Disorder              EPI          Collagen      Ristocetin

VWD                       N              N              [down arrow],
                                                         N or  [up
                                                         arrow]
Glanzmann throm-          [down arrow]   [down arrow]   N
 basthenia                 or Abs         or Abs
Bernard-soulier syn-      N              N              [down arrow]
 drome                                                   or Abs
Dense granule plate-      N or [down     N or [down     N
 let storage pool          arrow]         arrow]
 disorder ([delta]-SPD)
 [alpha]-SPD               N              Var [down     N
                                          arrow]
Signal transduction       Var [down      Var [down      N
 disorders                 arrow]         arrow]
Aspirin-like drug or      [down arrow]   [down arrow]   N
 defects of throm-                        or Abs
 boxane synthesis
Myeloproliferative        [down arrow]   N              N
 disorder                  or Abs
                           delayed lag
Scott syndrome            N              N              N
Uremia                    N/[down        N/[down        N
                           arrow]         arrow]
Thienopyridines (ti-      N              N              N
 clopidine and clo-
 pidogrel)
GP IIb/IIIa antago-       [down arrow]   [down arrow]   N
 nists                     or Abs         or Abs

        Disorder                  Other Studies

VWD                      Factor VIII:C, VWF antigen, VWF
                          risocetin cofactor, VWF multimers

Glanzmann throm-         Deficiency of GP IIb and/or GP
 basthenia                IIIa by flow cytometry
Bernard-soulier syn-     Macrothrombocytopenia
 drome                   Deficiency of GP Ib/IX/V (one or
                          more) by flow cytometry
Dense granule plate-     Decreased ATP release by
 let storage pool         lumiaggregometry
 disorder ([delta]-SPD)  [down arrow] Dense granule
                          mepacrine up-take and release
                          by flow cytometry
                         Decreased dense granules by
                          TEM
                         Abnormally high ATP/ADP ratio
                         Acquired SPD "exhausted platelets"
                          (CPB, DIC, TTP, HUS,
                          MPD)
                         Albinism in Hermansky-Pudlak
                          and Chediak-Higashi
                         Infections, small platelets seen
                          with Wiskott-Aldrich
[alpha]-SPD              Pale platelets on smear, [down
                          arrow] alpha granules by TEM,
                          [down arrow] P-selectin
Signal transduction      Decreased granule release with
 disorders                normal number of granules
                         Receptor defects may show [down
                          arrow] aggregation to EPI,
                          collagen only
                         [down arrow] G-protein activation,
                          tion, phospholipase C activation,
                          calcium mobilization,
                          pleckstrin, or tyrosine
                          phosphorylation
Aspirin-like drug or     Normal aggregation with prostaglandin
 defects of throm-        [G.sub.2] seen with
 boxane synthesis         aspirin or cyclooxygenase
                          deficiency
                         Decreased or absent prostaglandin
                          [G.sub.2] aggregation with
                          thromboxane synthetase deficiency

Myeloproliferative       Other abnormalities: [alpha] or
 disorder                 [delta]-SPD, cyclooxygenase
                          abnormality, other surface GP
                          derangements, [down arrow] or
                          [up arrow] aggregation to ADP,
                          collagen, spontaneous
                          aggregation
Scott syndrome           Defective platelet procoagulant
                          activity (ie, PF3)
                         Defective microparticle formation

Uremia                   Abnormal creatinine, BUN
                         Decreased PF3
Thienopyridines (ti-     History of clopidogrel or
 clopidine and clo-       ticlopidine therapy
 pidogrel)
GP IIb/IIIa antago-      History of treatment; abciximab,
 nists                    tirofiban, or eptifibatide
                         Increased receptor occupancy
                          by flow cytometry

* ADP indicates adenosine diphosphate; AA, arachidonic acid;
EPI, epinephrine; VWD, von Willebrand disease; Abs, absent;
GP, glycoprotein; ATP, adenosine triphosphate; TEM,
transmission electron microscopy; CPB, cardiopulmonary bypass;
DIC, disseminated intravascular coagulation; TTP, thrombotic
thrombocytopenic purpura; HUS, hemolytic uremic syndrome;
MPD, myeloproliferative disease; Var, variable response; PF3,
platelet factor 3; and BUN, blood urea nitrogen. Up and down
arrows indicate increased and decreased, respectively.


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  • William de Albini or William d'Albini

This page or section lists people with the surname Albini.
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microangiopathic hemolytic anemia.
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ELISA
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(99.) Furlan M, Robles Robles is a common surname in the Spanish language meaning oaks, and may refer to:
  • Alfonso García Robles (1911-1991), Mexican diplomat and politician
  • Aurora Robles (born 1980), Mexican fashion model
  • Charlie Robles (born 1943), Puerto Rican musician
 R, Galbusera M, et al. von Willebrand factor--cleaving protease protease /pro·te·ase/ (pro´te-as) endopeptidase.

pro·te·ase
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Any of various enzymes, including the proteinases and peptidases, that catalyze the hydrolytic breakdown of proteins.
 in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339:1578-1584.

(100.) George JN, Vesely SK, Rizvi MA. Thrombotic thrombocytopenic purpurahemolytic uremic uremic

pertaining to or emanating from uremia.


uremic poisoning
see uremia, visceral gout.

uremic toxins
 syndrome. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 4th ed. Phladelphia, Pa: JB Lippincott Co; 2001:1235-1242.

(101.) Boyce TG, Swerdlow DL, Griffin PM. Escherichia coil O157:h7 and the hemolytic-uremic syndrome. N Engl J Med. 1994;333:364-368.

(102.) Bennett CL, Connors JM, Carwile JM. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000;342:1773-1777

(103.) Atkinson K, Biggs JC, Hayes J, et al. Cyclosporin A associated nephrotoxicity neph·ro·tox·ic·i·ty
n.
The quality or state of being toxic to kidney cells.


nephrotoxicity(ne·fr
 in the first 100 days after allogeneic allogeneic /al·lo·ge·ne·ic/ (-je-ne´ik)
1. having cell types that are antigenically distinct.

2. in transplantation biology, denoting individuals (or tissues) that are of the same species but antigenically
 bone marrow transplantation Bone Marrow Transplantation Definition

The bone marrow—the sponge-like tissue found in the center of certain bones—contains stem cells that are the precursors of white blood cells, red blood cells, and platelets.
: three distinct syndromes. Br J Haematol. 1983;54:59-67.

(104.) Jandl JH. Disorders of platelets. In: Blood: Textbook of Hematology. 2nd ed. Boston, Mass: Little Brown; 1996:1301-1360.

(105.) Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute profound thrombocytopenia after c7E3 Fab (Abciximab) therapy. Circulation. 1997;95:809-813.

(106.) Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost. 1998;79:1-7.

(107.) Greinacher A, Amiral J, Dummel V, Vissac A, Kiefel V, Mueller-Eckhardt C. Laboratory diagnosis of heparin-associated thrombocytopenia and comparison of platelet aggregation test Platelet Aggregation Test Definition

Platelets are disk-shaped blood cells that are also called thrombocytes. They play a major role in the blood-clotting process. The platelet aggregation test is a measure of platelet function.
, heparin-induced platelet activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay. Transfusion. 1994;34:381-385.

(108.) Mammen EF. Sticky platelet syndrome. Semin Thromb Hemost. 1999;25: 361-365.

(109.) Knight CJ, Panesar M, Wright C, et al. Altered platelet function detected by flow cytometry: effects of coronary artery disease and age. Arterioscler Thromb Vasc Biol. 1997;17:2044-2053.

(110.) Blann AD, Lip GY. Platelets and hypertension; the pressure is on the clot. J Hum Hypertens. 1997;11:763-764

(111.) Winocour PD. Platelet abnormalities in diabetes mellitus. Diabetes. 1992; 41:26-31.

(112.) Mustard JF, Packham MA. Platelets and diabetes mellitus. N Engl J Med. 1984;311:665-667.

(113.) Riondino S, Pignatelli P, Pulcinelli FM, et al. Platelet hyperactivity in hypertensive older patients is controlled by lowering BP. J Am Geriatr Soc. 1999; 47:943-947.

(114.) Wu KK, Hoak JC. A new method for the quantitative detection of platelet aggregates in patients with arterial insufficiency. Lancet. 1974;2:924-926.

Accepted for publication September 7, 2001.

From the Department of Clinical Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio.

Reprints: Kandice Kottke-Marchant, MD, PhD, Department of Clinical Pathology, The Cleveland Clinic Foundation, L30, 9500 Euclid Ave, Cleveland, OH 44195 (e-mail: marchak@ccf.org).
COPYRIGHT 2002 College of American Pathologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2002 Gale, Cengage Learning. All rights reserved.

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Author:Kottke-Marchant, Kandice; Corcoran, George
Publication:Archives of Pathology & Laboratory Medicine
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Date:Feb 1, 2002
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