Page 2018 - Williams Hematology ( PDFDrive )

1993

CHAPTER 117 to be identified. Many early investigators are associated with the dis-
covery of blood platelets, including Donné, Hayem, Bizzozero, and
THROMBOCYTOPENIA Osler, but it was James Homer Wright who, in 1906, using his spe-
cial stain (later called Wright stain), described the morphology of
platelets with their central granular area and marginal hyaline zone
and established that they were the product of the fragmentation of
Reyhan Diz-Küçükkaya and José A. López marrow megakaryocytes. Clot retraction was discovered long before
platelets, but Hayem, through a series of studies, showed retraction
to be dependent on platelets. During the mid-20th century the aggre-
SUMMARY gation of platelets, their adherence to collagen of damaged tissues,
their acceleration of blood coagulation, and their relationship to the
bleeding time and the biochemistry underlying several of these pro-
Thrombocytopenia is one of the most frequent causes for hematologic consul- cesses were described by scientists, among whom were Paul Owren,
tation in the practice of medicine, and may be life threatening. Although the Kenneth Brinkhaus, Edwin Chargaff, Ernst Lüsher, Marjorie Zucker,
normal platelet count in humans (150 to 400 × 10 /L) far exceeds the minimal and William Duke.
9
level required to avoid pathologic hemorrhage (<50 × 10 /L), a number of Platelets circulate in close contact with the endothelium, contin-
9
medical conditions either increasing the destruction of platelets or reduc- ually monitoring its integrity. When the vessel wall is damaged, plate-
ing their production, enhance the risk of bleeding. This chapter discusses an lets bind to subendothelial proteins, initiating the process of primary
approach to the diagnosis of thrombocytopenia, grouping various causes by hemostasis. At sites of blood loss, the platelets aggregate to form a vessel
mechanism of action, and describing our current understanding of the patho- sealing plug to halt bleeding. Activated platelets at sites of injury also
genesis, treatment and prognosis. In the vast majority of patients, a cause for provide a surface for assembly of coagulation reactions, resulting in the
production of fibrin and consolidation of the thrombus. Both qualita-
thrombocytopenia can be identified, and effective therapy instituted. tive and quantitative deficiencies of the platelets cause bleeding. Plate-
lets also have important functions in inflammation, tissue remodeling
and wound healing. 1
Approximately 1 × 10 platelets are produced per day by an adult
11
DEFINITION AND HISTORY human, a number that can be increased 20-fold or more, if necessary.
2
Platelets are anucleate blood cells produced in the marrow by poly- One-third of the platelets are stored in the spleen, the remaining two-
3
ploid cells termed megakaryocytes and were described in the 19th thirds circulate in blood vessels. Disorders that increase splenic volume
century after the application of the improved compound microscope cause more platelets to be trapped in the spleen, lowering the concen-
allowed these very small cellules, approximately 2 μM in diameter, tration of circulating platelets, although alone, this redistribution rarely
causes a significant bleeding diathesis.
Under normal conditions, human platelets have a mean life span
4,5
in the circulation of between 7 and 10 days. Patients with thrombo-
Acronyms and Abbreviations: ACOG, American College of Obstetricians and Gyne- cytopenia secondary to platelet destruction have a markedly decreased
6,7
cologists; ADP, adenosine diphosphate; AFLP, acute fatty liver of pregnancy; AML, platelet survival. Patients with thrombocytopenia from marrow fail-
acute myelogenous leukemia; APLA, antiphospholipid antibody; APS, antiphospho- ure have mildly decreased platelet survival, mostly because the body’s
lipid syndrome; ARC, arthrogryposis–renal dysfunction–cholestasis; ASH, Ameri- fixed daily consumption of platelets accounts for a progressively larger
can Society of Hematology; ATG, antithymocyte globulin; ATRUS, amegakaryocytic fraction of the reduced total daily production as the platelet count
8
thrombocytopenia with radioulnar synostosis; CAMT, congenital amegakaryocytic drops. Platelet turnover is a measure of the net effect of platelet pro-
7
thrombocytopenia; CAPTURE, c7E3 Fab Antiplatelet Therapy in Unstable Refractory duction and platelet destruction under steady-state conditions. Sev-
111
Angina; CTP, cyclic thrombocytopenia; CVID, common variable immunodeficiency; eral studies using In oxine–labeled platelets have established that,
DIC, disseminated intravascular coagulation; EDTA, ethylenediaminetetraacetic acid; under normal conditions, platelet turnover in humans ranges from 40
9
7
EPIC, Evaluation of 7E3 for the Prevention of Ischemic Complications; EPILOG, Evalua- to 50 × 10 /L per day. Although a high platelet turnover is expected
tion of Percutaneous Transluminal Coronary Angioplasty to Improve Long-term Out- in patients with immune thrombocytopenia (ITP), platelet produc-
7
come of c7E3 GPIIb-IIIa Receptor Blockade; EPISTENT, Evaluation of Platelet IIb/IIIa tion is not always increased in this disorder. Low platelet production
Inhibitor for Stenting; Flt1, fms-like tyrosine kinase-1; FPD/AML, familial platelet dis- may result from binding of the antiplatelet antibodies to megakary-
order with propensity to acute myeloid malignancy; GP, glycoprotein; HCV, hepatitis C ocytes, inhibiting their maturation or leading to their destruction,
virus; HELLP, hemolysis, elevated liver enzymes, low platelets; HIT, heparin-induced causing an inappropriately muted marrow response to the degree of
thrombocytopenia; HUS, hemolytic uremic syndrome; HPA, human platelet allo- thrombocytopenia. 9
antigen; ICSH, International Council for Standardization in Hematology; IDA, iron- Every day approximately 10 to 12 percent of circulating platelets
deficiency anemia; IPD, inherited platelet disorder; ITP, immune thrombocytopenia; are removed by the mononuclear phagocyte system, primarily by mac-
IVIG, intravenous immunoglobulin; IWG, International Working Group; LTA, light rophages in the spleen and liver. Although the precise mechanisms of
transmission aggregometry; MACE, modified antigen capture enzyme-linked ımmu- platelet clearance are not completely understood, changes that occur as
nosorbent assay; MAIPA, monoclonal antibody-specific immobilization of platelet the platelets circulate are thought to lead them to be recognized by mac-
antigens; MDS, myelodysplastic syndrome; MHC, major histocompatibility complex; rophages. One of these changes is the progressive loss of sialic acid from
NAIT, neonatal alloimmune thrombocytopenia; PAIgG, platelet-associated immuno- platelet surface proteins. Studies in animals and humans with antican-
globulin G; sFlt1, soluble Flt1; SLE, systemic lupus erythematosus; TAR, thrombocy- cer drugs that inhibit apoptotic pathways have also identified a role for
topenia with absent radii; TPO, thrombopoietin; Treg, T-regulatory; TTP, thrombotic apoptotic proteins in platelet survival and clearance. According to these
thrombocytopenic purpura; VEGF, vascular endothelial growth factor; VWD, von studies, a classical intrinsic apoptosis pathway regulates the life span of
Willebrand disease; VWF, von Willebrand factor. circulating platelets, and antiapoptotic proteins, especially Bcl- , main-
XL
tain platelet viability by restraining apoptosis. 10

Kaushansky_chapter 117_p1993-2024.indd 1993 9/21/15 2:31 PM