Page 2087 - Williams Hematology ( PDFDrive )

2062 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2063

dysfunction. 585,587,588 Most patients with thrombasthenia do not respond along the septum or the lateral nasal wall. Self-administered home
to DDAVP with a shortening of the bleeding time 585,587–589 with excep- therapy for anterior hemorrhage consists of pinching the outer aspect
590
tions, but it is unknown whether DDAVP improves hemostasis of the nose against the septum for 15 minutes to tamponade the sep-
608
in these patients despite a lack of shortening of the bleeding time. tal vessels. If this fails, topical application by medical personnel of
Responses to DDAVP in SPD patients have been variable with a short- an anesthetic such as lidocaine in combination with a vasoconstrictor
ening of the bleeding time in some patients 588,591 but not others. 585,587 In such as phenylephrine or oxymetazoline is commonly effective. Electri-
uncontrolled studies it has been feasible to manage selected patients cal cautery sometimes is effective when chemical cauterization fails. In
with inherited platelet defects undergoing surgical procedures with many cases anterior or posterior packing may be needed for persistent
DDAVP alone. 585,587 However, this approach needs to be individualized severe epistaxis.
based on the nature and location of the surgery and the intensity of Menarche may be associated with the severe bleeding manifesta-
the patient’s bleeding symptoms, and platelet need to be readily avail- tions and require transfusions in some patients. Antifibrinolytics have
able for transfusion in the event of excess hemorrhage. The abnormal been used for menorrhagia; hormonal therapy with progesterone alone
in vitro platelet aggregation or secretion responses in patients with or combined progesterone-estrogen is effective in those with persistent
platelet defects are usually not corrected by DDAVP. 587,592 It has been hemorrhage. 581,583
proposed that one mechanism by which DDAVP improves platelet
function is via increased formation of procoagulant “COAT” platelets PREGNANCY
induced by combined activation by collagen and thrombin. 592 Management during pregnancy and delivery requires close interac-
Investigators have reported the successful use of recombinant fac- tion between the hematologist and the obstetrician. Most patients with
tor VIIa (rFVIIa) in the management of bleeding events in patients with severe bleeding symptoms, particularly those with GT and the BSS, will
inherited platelet defects, including GT (including patients with anti- need platelet transfusions during childbirth and this need may continue
bodies to integrin α β ), the BSS and SPD. 581,583,593–596 rFVIIa is thought for several days after delivery. 581–583 Postpartum bleeding may occur
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to increase thrombin generation through both tissue factor dependent 2 to 4 weeks after delivery in some patients. rFVIIa has been used suc-
and independent mechanisms. cessfully in women with GT with persistent bleeding despite platelet
The antifibrinolytic agents epsilon-aminocaproic acid (EACA) and transfusions, and those with integrin α β antibodies. 581–583,609,610 Of
tranexamic acid, 581–583 which may be given orally, intravenously, or top- note, fetal thrombocytopenia and intracranial hemorrhage may occur
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ically have been successfully used in patients with coagulation disorders because of transplacental passage of the antibodies.
and platelet function abnormalities. 586,597 Antifibrinolytic agents are useful
in patients with gingival bleeding, epistaxis, and menorrhagia, and those
undergoing dental extractions. A tranexamic acid mouthwash (10 mL of SURGERY
a 5 percent solution used four times daily) has been found effective in Management during surgical procedures needs to be individualized and
582
controlling gum bleeding and bleeding after tooth extractions. A short depends on the bleeding history of the patient, the nature of the surgery,
598
3- to 4-day course of prednisone (20 to 50 mg) has also been used. and on information such as alloimmunization and refractoriness to
Topical agents can also help arrest bleeding and have been used in prior transfusions. Therapeutic options include DDAVP, platelet trans-
GT patients. Gelfoam (a form of resolvable, oxidized, regenerated cel- fusions, rFVIIa and ancillary measures, such as antifibrinolytics, which
lulose) soaked in either tranexamic acid or topical thrombin may be may be continued for several days postsurgery. 581–583
effective. Fibrin sealants prepared from a source of fibrinogen and a
599
source of thrombin (exogenous or from the patient’s own plasma), with
599
or without antifibrinolytic agents or other components have been REFERENCES
used successfully in patients with GT. Some preparations of bovine
600
thrombin induced antibody formation to itself and contaminated fac- 1. Noris P, Biino G, Pecci A, et al: Platelet diameters in inherited thrombocytopenias:
Analysis of 376 patients with all known disorders. Blood 124:e4–e10, 2014.
tor V and factor XI and have been associated with serious hemorrhage; 2. Kumar R, Kahr WHA: Congenital thrombocytopenia: Clinical manifestations, labo-
recombinant human thrombin is now available and appears to have low ratory abnormalities, and molecular defects of a heterogeneous group of conditions.
immunogenicity. 601 Hematol Oncol Clin N Am 27:465–494, 2013.
Allogeneic marrow transplantation has successfully in treated 3. Harrison P, Lordkipanidze M: Clinical tests of platelet function in AD, editor. Platelets,
Third Edition, edited by AD Michelson, pp 519–545. Elsevier, San Diego, CA, 2013.
patients with GT, BSS, LAD-3, and WAS. 523,524 Progress has been 4. Cattaneo M, Hayward CP, Moffat KA, et al: Results of a worldwide survey on the assess-
541
581
made in gene therapy approaches to correcting the genetic defect in ment of platelet function by light transmission aggregometry: A report from the platelet
physiology subcommittee of the SSC of the ISTH. J Thromb Haemost 7:1029, 2009.
GT in megakaryocytes. 602–604 Several GT animal models are available, 5. Hayward CP, Moffat KA, Spitzer E, et al: Results of an external proficiency testing exer-
605
including the integrin subunits α and β -null mouse models, and cise on platelet dense-granule deficiency testing by whole mount electron microscopy.
3
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dog models involving mutations in the α subunit. 604,606,607 With respect Am J Clin Pathol 131:671–675, 2009.
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to BSS, in mouse models, lentiviral transduction of hematopoietic stem 6. Hayward CP, Pai M, Liu Y, et al: Diagnostic utility of light transmission platelet
cells with human GPIbα under the control of the integrin α promoter aggregometry: Results from a prospective study of individuals referred for bleeding
disorder assessments. J Thromb Haemost 7:676–684, 2009.
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has been effective in improving hemostasis when transplanted into ani- 7. Flamm MH, Colace TV, Chatterjee MS, et al: Multiscale prediction of patient-specific
289
mals. Thus, as methods of marrow transplantation and gene trans- platelet function under flow. Blood 120:190–198, 2012.
fer therapy improve, it will be important to reassess the risk-to-benefit 8. de Witt SM, Swieringa F, Cavill R, et al: Identification of platelet function defects by
multi-parameter assessment of thrombus formation. Nat Commun 5:4257, 2014.
ratios of these therapies for individual patients with GT. 9. Stockley J, Morgan NV, Bem D, et al: Enrichment of FLI1 and RUNX1 mutations in
families with excessive bleeding and platelet dense granule secretion defects. Blood
122:4090–4093, 2013.
BLEEDING AT SPECIFIC SITES 10. Albers CA, Cvejic A, Favier R, et al: Exome sequencing identifies NBEAL2 as the caus-
ative gene for gray platelet syndrome. Nat Genet 43:735–737, 2011.
Control of epistaxis can be particularly difficult in some patients. 11. Kahr WH, Hinckley J, Li L, et al: Mutations in NBEAL2, encoding a BEACH protein,
608
When topical measures fail, platelet transfusions or factor VIIa should cause gray platelet syndrome. Nat Genet 43:738–740, 2011.
be considered. Nosebleeds occur primarily along the anterior nasal sep- 12. Gunay-Aygun M, Falik-Zaccai TC, Vilboux T, et al: NBEAL2 is mutated in gray plate-
let syndrome and is required for biogenesis of platelet alpha-granules. Nat Genet 43:
tum at the Kiesselbach area, posterior nosebleeds can occur either 732–734, 2011.
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