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2060 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2061

FLI-1 (DIMORPHIC DYSMORPHIC PLATELETS hexokinase deficiency, glucose-6 phosphatase deficiency (glycogen
566
WITH GIANT Α-GRANULES AND storage disease, type I), 567,568 and the Down syndrome. 569–573 In glu-
cose-6 phosphatase deficiency the platelet abnormalities were reversed
THROMBOCYTOPENIA (PARIS-TROUSSEAU/ following total parenteral nutrition for 10 to 12 days 567,568 indicating
JACOBSEN SYNDROME]) that the platelets may be intrinsically normal. The MYH9-related
disorders (May-Hegglin anomaly) are characterized by giant plate-
The Paris-Trousseau syndrome, a variant of Jacobsen syndrome, is a
rare autosomal dominant disorder 559–562 characterized by mental retar- lets, thrombocytopenia, and basophilic granulocyte inclusions; some
dation, congenital macrothrombocytopenia, giant α granules (1 to 2 μm patients with this anomaly have platelet function and ultrastruc-
8,574,575
in diameter) in a subpopulation (1 to 5 percent) of circulating platelets, tural abnormalities. Despite the large platelet size, the surface
576
and marrow dysmegakaryopoiesis in association with deletion of the membrane glycoproteins appear to be normal. Markedly impaired
distal part of either the maternally or paternally derived chromosome platelet responses to multiple agonists have been reported with par-
11 (11q23.3–24). Among the genes deleted is the transcription factor tial trisomy 18p associated with three copies of the PACAP (pituitary
FLI1, which is important in megakaryocyte development via its effects adenylate cyclase-activating polypeptide) gene and elevated plasma
on expression of several genes, including ITGA2, GPIX, GPIbα, and levels of PACAP, which induces increased platelet cAMP levels via
577
2
c-MPL. Although platelet survival is normal, there is dramatic expan- stimulation of Gαs.
sion of marrow megakaryocytes resulting from arrested megakaryocyte Familial hemophagocytic lymphohistiocytosis (FHLH) is a genetic
development. Thrombin-induced platelet release of α-granule contents disorder of lymphocyte cytotoxicity associated with mutations in the
is impaired. Both the inheritance pattern and the dimorphic popula- gene encoding perforin or proteins important for vesicular traffick-
559
tion of normal and dysmorphic giant α granules are explained by the ing and exocytosis. Flow cytometric analyses of the platelets of FHLH
observation that during a period in early megakaryocyte development, type 5 patients, who have MUNC18–2 (STXBP2) mutations, revealed
only one of the two FLI1 alleles appears to be expressed in any single that thrombin-induced secretion from both α and δ granules is
578,579
megakaryocyte precursor. 561,562 impaired. Platelets from an FHLH type 4 patient with a mutation
in syntaxin-11 (STX11) also had a defect in agonist-induced secretion
associated with normal cargo levels. 580
GFI1B
Two studies 419,420 implicate autosomal dominant mutations in GFI1B
with a bleeding disorder and multiple alterations in platelet number and MANAGEMENT OF INHERITED
function, and red cell anisopoikilocytosis. In one study, the affected PLATELET FUNCTION DISORDERS
420
family members had a single nucleotide insertion in exon 7 of GFI1B
leading to a frameshift mutation associated with macrothrombocytope- Management of patients with inherited platelet function disorders
nia, impaired platelet aggregation responses, α-granule deficiency, and needs to be individualized because of the wide variation in clinical man-
decreased platelet P-selectin, fibrinogen, GPIbα, and integrin β . The ifestations, even in patients with the same defect. A general approach
3
second study identified a dominant-negative truncating mutation is described here; additional features specific to some individual enti-
419
(c.859C to T) in the zinc finger 5 region of GFI1B in a family originally ties are provided in their respective descriptions. Management of these
reported in 1968 with macrothrombocytopenia and platelet dysfunc- patients involves preventive measures and treatment of specific bleed-
tion. The family members had decreased platelet α granules, PF4, ing episodes. 581–583 Dental hygiene is important in minimizing gingival
563
βTG, and GP1bα, and deficiency of platelet factor 3. There was myelofi- hemorrhage. Antiplatelet agents should be avoided as they increase
brosis and emperipolesis in the marrow. the bleeding manifestations. Iron and folate supplementation may be
needed in patients with chronic hemorrhage. Hepatitis B vaccine should
be administered early in life.
MISCELLANEOUS INHERITED
DISORDERS ASSOCIATED WITH PLATELET TRANSFUSIONS AND GENERAL
PLATELET FUNCTION DEFECTS APPROACHES
Transfusion of platelets (Chap. 139) is a time-tested therapy for serious
The TAR syndrome is characterized by a reduction in platelet counts, bleeding and as prophylaxis prior to surgery or invasive procedures. In
absence of the radius bone in the forearm, skeletal abnormalities, addition to the usual risks associated with transfusions (transmission of
and decreased marrow megakaryocytes. Dense granule SPD and infections, allergic reactions, Rh-immunization in Rh-negative individ-
impaired platelet aggregation and secretion have also been reported uals, and rarely hemolytic reactions) patients with GT and the BSS may
in TAR syndrome. Early studies reported that majority of these develop specific antibodies against the missing glycoproteins, which
371
patients have a deletion on chromosome 1q21.1, and later studies may seriously compromise efficacy of future platelet transfusions. 581,582
15
showed that these patients have both a rare null allele of RBM8A This occurs particularly in patients whose platelets have no detectable
along with one of two low-frequency single nucleotide polymor- integrin α β . Therefore, platelet transfusions should be kept to a
584
IIb 3
phisms (SNPs) in the gene’s regulatory regions. RBM8A encodes minimum. Transfusions of both platelets and red blood cells should
14
for the Y14 subunit of the exon-junction complex (EJC), which plays be given with leukocyte depletion filters to decrease the risk of alloim-
an essential in RNA processing. munization and cytomegalovirus transmission. It is reasonable to use
Platelet function abnormalities have also been reported in inher- human leukocyte antigen (HLA)-matched and ABO-matched platelets
ited connective tissue disorders such as osteogenesis imperfecta, the to minimize the risk of alloimmunization and side effects. 581–583
Ehlers-Danlos syndrome, and the Marfan syndrome 369,370,564,565 ; bleed- Treatment with 1-deamino-8-d-arginine vasopressin (DDAVP;
ing manifestations are more likely caused by the underlying connec- desmopressin) may shorten the bleeding time and/or improve hemo-
tive tissue defect than by the platelet dysfunction. Abnormalities in stasis in some, but not all, patients with platelet function defects. 585–588
platelet responses and or granules have been reported in patients with Responses to DDAVP appear dependent on the cause of the platelet

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