Glanzmann's thrombasthenia

Glanzmann's thrombasthenia
Classification and external resources
Specialty	hematology
ICD-10	D69.1
ICD-9-CM	287.1
OMIM	187800 273800
DiseasesDB	5224
MedlinePlus	001305
eMedicine	med/872
MeSH	D013915

Glanzmann's thrombasthenia is an abnormality of the platelets.^[1] It is an extremely rare coagulopathy (bleeding disorder due to a blood abnormality), in which the platelets contain defective or low levels of glycoprotein IIb/IIIa (GpIIb/IIIa), which is a receptor for fibrinogen. As a result, no fibrinogen bridging of platelets to other platelets can occur, and the bleeding time is significantly prolonged.

Signs and symptoms

Characteristically, there is increased mucosal bleeding:^[2]

menorrhagia
easy bruising
epistaxis
gingival bleeding
gastrointestinal bleeding
postpartum bleeding
increased bleeding post-operatively.

The bleeding tendency is variable but may be severe. Hemarthrosis, particularly spontaneous, is very rare, in contrast to the hemophilias.

Platelet numbers and morphology are normal. Platelet aggregation is normal with ristocetin, but impaired with other agonists such as ADP, thrombin, collagen or epinephrine.

Laboratory findings in various platelet and coagulation disorders (V - T)
Condition	Prothrombin time	Partial thromboplastin time	Bleeding time	Platelet count
Vitamin K deficiency or warfarin	Prolonged	Normal or mildly prolonged	Unaffected	Unaffected
Disseminated intravascular coagulation	Prolonged	Prolonged	Prolonged	Decreased
Von Willebrand disease	Unaffected	Prolonged or unaffected	Prolonged	Unaffected
Hemophilia	Unaffected	Prolonged	Unaffected	Unaffected
Aspirin	Unaffected	Unaffected	Prolonged	Unaffected
Thrombocytopenia	Unaffected	Unaffected	Prolonged	Decreased
Liver failure, early	Prolonged	Unaffected	Unaffected	Unaffected
Liver failure, end-stage	Prolonged	Prolonged	Prolonged	Decreased
Uremia	Unaffected	Unaffected	Prolonged	Unaffected
Congenital afibrinogenemia	Prolonged	Prolonged	Prolonged	Unaffected
Factor V deficiency	Prolonged	Prolonged	Unaffected	Unaffected
Factor X deficiency as seen in amyloid purpura	Prolonged	Prolonged	Unaffected	Unaffected
Glanzmann's thrombasthenia	Unaffected	Unaffected	Prolonged	Unaffected
Bernard-Soulier syndrome	Unaffected	Unaffected	Prolonged	Decreased or unaffected
Factor XII deficiency	Unaffected	Prolonged	Unaffected	Unaffected
C1INH deficiency	Unaffected	Shortened	Unaffected	Unaffected

Cause

Glanzmann's thrombasthenia can be inherited in an autosomal recessive manner^[2]^[3] or acquired as an autoimmune disorder.^[2]^[4]

The bleeding tendency in Glanzmann's thrombasthenia is variable,^[2] some individuals having minimal bruising, while others have frequent, severe, potentially fatal hemorrhages. Moreover, platelet α_IIbβ₃ levels correlate poorly with hemorrhagic severity, as virtually undetectable α_IIbβ₃ levels can correlate with negligible bleeding symptoms, and 10%–15% levels can correlate with severe hemorrhage.^[5] Unidentified factors other than the platelet defect itself may have important roles.^[2]

Pathophysiology

Glanzmann's thrombasthenia is associated with abnormal glycoprotein IIb/IIIa (GpIIb/IIIa), also known as α_IIbβ₃, which is an integrin aggregation receptor on platelets. This receptor is activated when the platelet is stimulated by ADP, epinephrine, collagen, or thrombin. GpIIb/IIIa is essential to blood coagulation since the activated receptor has the ability to bind fibrinogen (as well as von Willebrand factor, fibronectin, and vitronectin), which is required for fibrinogen-dependent platelet-platelet interaction (aggregation).

In contrast, glycoprotein Ib receptors are normal with Glanzmann's thrombasthenia. The role of GpIb is to enable platelet activation by contact with the von Willebrand factor-collagen complex that is exposed when the endothelial blood vessel lining is damaged.

Understanding of the role of GpIIb/IIIa in Glanzmann's thrombasthenia led to the development of GpIIb/IIIa inhibitors, a class of powerful antiplatelet agents.^[3]

Treatment

Therapy involves both preventive measures and treatment of specific bleeding episodes.^[2]

Dental hygiene lessens gingival bleeding^[6]
Avoidance of antiplatelet agents such as aspirin and other anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen, and anticoagulants
Iron or folate supplementation may be necessary if excessive or prolonged bleeding has caused anemia
Hepatitis B vaccine
Antifibrinolytic drugs such as tranexamic acid or ε-aminocaproic acid (Amicar)
Desmopressin (DDAVP) does not normalize the bleeding time in Glanzmann's thrombasthenia but anecdotally improves hemostasis
Hormonal contraceptives to control excessive menstrual bleeding
Topical agents such as gelfoam, fibrin sealants, polyethylene glycol polymers, custom dental splints
Platelet transfusions (only if bleeding is severe; risk of platelet alloimmunization)
Recombinant factor VIIa, AryoSeven or NovoSeven FDA approved this drug for the treatment of the disease on July 2014.
Hematopoietic stem cell transplantation (HSCT) for severe recurrent hemorrhages

Eponym

It is named after Eduard Glanzmann (1887-1959), the Swiss pediatrician who originally described it.^[7]^[8]^[9]

References

↑ "Glanzmann thrombasthenia" at Dorland's Medical Dictionary
1 2 3 4 5 6 Kaushansky K, Lichtman M, Beutler E, Kipps T, Prchal J, Seligsohn U. (2010; edition 8: pages 1933-1941) Williams Hematology. McGraw-Hill.ISBN 978-0071621519
1 2 Seligsohn U (2002). "Glanzmann thrombasthenia: a model disease which paved the way to powerful therapeutic agents" (PDF). Pathophysiol. Haemost. Thromb. 32 (5-6): 216–7. doi:10.1159/000073569. PMID 13679645.
↑ Tholouli E, Hay CR, O'Gorman P, Makris M (2004). "Acquired Glanzmann's thrombasthenia without thrombocytopenia: a severe acquired autoimmune bleeding disorder". Br. J. Haematol. 127 (2): 209–13. doi:10.1111/j.1365-2141.2004.05173.x. PMID 15461628.
↑ Nurden, A. T. (2006). "Glanzmann thrombasthenia". Orphanet Journal of Rare Diseases 1: 10. doi:10.1186/1750-1172-1-10. PMC 1475837. PMID 16722529.
↑ F.Z. Elmouatarif, B. Badre, S. Elarabi (2013). "Thrombasthénie de Glanzmann". Le courrier du dentiste.
↑ synd/1289 at Who Named It?
↑ Glanzmann, WE (1918). "Hereditäre hämorrhagische Thrombasthenie. Ein Beitrag zur Pathologie der Blutplättchen.[Hereditary haemorrhagic thrombasthenia. A contribution to the pathology of platelets] (German)". Jahrbuch für Kinderheilkunde [Yearbook of Pediatrics] 88 (1-42): 113–141.
↑ Kannan, M.; Saxena, R. (2009). "Glanzmann's thrombasthenia: an overview". Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 15 (2): 152–165. doi:10.1177/1076029608326165. PMID 18930954.

External links

Internet database of mutations giving rise to Glanzmann's thrombasthenia:

Diseases of red blood cells and clotting (D50–69,74, 280–287)

Red
blood cells

↑

Polycythemia	Polycythemia vera

↓

Anemia

Nutritional

Micro-: Iron-deficiency anemia
- Plummer–Vinson syndrome

Macro-: Megaloblastic anemia
- Pernicious anemia

Hemolytic
(mostly normo-)

Hereditary	enzymopathy: G6PD glycolysis PK TI HK hemoglobinopathy: Thalassemia alpha beta delta Sickle-cell disease/trait HPFH membrane: Hereditary spherocytosis Minkowski–Chauffard syndrome Hereditary elliptocytosis Southeast Asian ovalocytosis Hereditary stomatocytosis

Acquired	Autoimmune WAHA CAD PCH membrane PNH MAHA TM HUS Drug-induced autoimmune Drug-induced nonautoimmune Hemolytic disease of the newborn

Aplastic
(mostly normo-)

Blood tests

MCV
MCHC
- Normochromic
- Hypochromic

Other

Coagulation/
coagulopathy

↑

Hyper- coagulability	primary: Antithrombin III deficiency Protein C deficiency/Activated protein C resistance/Protein S deficiency/Factor V Leiden Prothrombin G20210A Sticky platelet syndrome acquired:Thrombocytosis essential DIC Purpura fulminans autoimmune Antiphospholipid

↓

Hypo-
coagulability

Thrombocytopenia	Thrombocytopenic purpura: ITP Evans syndrome TM TTP Upshaw Schulman syndrome Heparin-induced thrombocytopenia May–Hegglin anomaly

Platelet function	adhesion Bernard–Soulier syndrome aggregation Glanzmann's thrombasthenia platelet storage pool deficiency Hermansky–Pudlak syndrome Gray platelet syndrome

Clotting factor	Hemophilia A/VIII B/IX C/XI von Willebrand disease Hypoprothrombinemia/II XIII Dysfibrinogenemia Congenital afibrinogenemia

Cell surface receptor deficiencies

G protein-coupled receptor
(including hormone)

Class A	TSHR (Congenital hypothyroidism 1) LHCGR (Luteinizing hormone insensitivity, Leydig cell hypoplasia, Male-limited precocious puberty) FSHR (Follicle-stimulating hormone insensitivity, XX gonadal dysgenesis) GnRHR (Gonadotropin-releasing hormone insensitivity) EDNRB (ABCD syndrome, Waardenburg syndrome 4a, Hirschsprung's disease 2) AVPR2 (Nephrogenic diabetes insipidus 1) PTGER2 (Aspirin-induced asthma)

Class B	PTH1R (Jansen's metaphyseal chondrodysplasia)

Class C	CASR (Familial hypocalciuric hypercalcemia)

Class F	FZD4 (Familial exudative vitreoretinopathy 1)

Enzyme-linked receptor
(including
growth factor)

RTK	ROR2 (Robinow syndrome) FGFR1 (Pfeiffer syndrome, KAL2 Kallmann syndrome) FGFR2 (Apert syndrome, Antley–Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson–Weiss syndrome) FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome) INSR (Donohue syndrome Rabson–Mendenhall syndrome) NTRK1 (Congenital insensitivity to pain with anhidrosis) KIT (KIT Piebaldism, Gastrointestinal stromal tumor)

STPK	AMHR2 (Persistent Müllerian duct syndrome II) TGF beta receptors: Endoglin/Alk-1/SMAD4 (Hereditary hemorrhagic telangiectasia) TGFBR1/TGFBR2 (Loeys–Dietz syndrome)

GC	GUCY2D (Leber's congenital amaurosis 1)

JAK-STAT

MPL (Congenital amegakaryocytic thrombocytopenia)

TNF receptor

TNFRSF1A (TNF receptor associated periodic syndrome)
TNFRSF13B (Selective immunoglobulin A deficiency 2)
TNFRSF5 (Hyper-IgM syndrome type 3)
TNFRSF13C (CVID4)
TNFRSF13B (CVID2)
TNFRSF6 (Autoimmune lymphoproliferative syndrome 1A)

Lipid receptor

LRP: LRP2 (Donnai–Barrow syndrome)
LRP4 (Cenani–Lenz syndactylism)
LRP5 (Worth syndrome, Familial exudative vitreoretinopathy 4, Osteopetrosis 1)

LDLR (LDLR Familial hypercholesterolemia)

Other/ungrouped

Immunoglobulin superfamily: AGM3, 6

EDAR (EDAR hypohidrotic ectodermal dysplasia)

See also: cell surface receptors

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