Functional compensation of the low platelet count by increased individual platelet size in a patient with May-Hegglin anomaly presenting with acute myocardial infarction

Goto, Shinya; Kasahara, Hirofumi; Sakai, Hiroyuki; Goto, Masahisa; Ono, Miyuki; Ikeda, Yasuo; Jorquera, Juan I.; Bravo, M I; Handa, Shunnosuke

doi:10.1016/s0167-5273(98)00043-6

Cited by 16 publications

(12 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9,15 A requirement to bind 2 platelets per multimer implies that cleavage by ADAMTS13 should increase exponentially rather than linearly with platelet count (Figure 6), and it does (Figure 3). Shear-dependent binding of VWF to platelets 35 and shear-induced platelet aggregation 36 also show a similar nonlinear dependence on [25][26][27] plasma VWF concentration (ϳ10 g/mL), VWF subunit mass (ϳ250 kDa), and number of GPIb␣ per platelet (ϳ28 000). 26 The probability that a multimer has bound a particular number x of platelets is given by the binomial formula for P(x,n), where n is the number of VWF A1 domains (or subunits) per multimer and y is the fractional occupancy of VWF domain A1 sites by GPIb␣ ([GPIb␣-A1]/[A1]total): P(0,n) ϭ (1 Ϫ y) n and P(1,n) ϭ ny(1 Ϫ y) nϪ1 .…”

Section: Discussionmentioning

confidence: 99%

Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress

Shim

Anderson

Tuley

et al. 2008

Blood

149

144

View full text Add to dashboard Cite

Introductionvon Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays an essential role in tethering platelets at the site of vascular injury. VWF is synthesized in endothelial cells, where a portion is stored in granules called Weibel-Palade bodies as "unusually large" or "ultralarge" multimers (ULVWF) and secreted upon endothelial stimulation. 1,2 Secreted ULVWF multimers bind platelets with relatively high affinity and are thought to be prothrombotic. ULVWF is cleaved into smaller and less dangerous multimers by the metalloprotease ADAMTS13, a member of the A Disintegrin And Metalloprotease with ThromboSpondin type I repeat family. [3][4][5] Inherited or acquired deficiency of ADAMTS13 causes life-threatening microvascular thrombosis that is characteristic of thrombotic thrombocytopenic purpura. 4,6,7 Conversely, mutations in von Willebrand disease type 2A cause bleeding by increasing the cleavage of VWF by ADAMTS13 and impairing platelet adhesion. [8][9][10] Therefore, normal hemostasis depends on the precise regulation of VWF proteolysis.ADAMTS13 cleaves the Tyr 1605 -Met 1606 bond in the A2 domain of VWF, but this bond is buried and relatively inaccessible until the A2 domain is unfolded, presumably by tensile force in vivo. 10,11 The shear stress required to apply this force will vary depending on whether VWF is immobilized at the vessel wall or moving with the flowing blood, and whether platelets are bound to it. The rate of VWF cleavage also can be modulated by cofactors that bind to the A1 domain, including platelet GPIb and heparin. 12 Thus, ADAMTS13 is presented with VWF multimers in plasma or on endothelial cell surfaces that vary in their susceptibility to cleavage, with or without attached platelets.The relevance of each of these potential substrates to the catabolism of VWF is unknown. Several studies suggest that VWF strings on endothelial cells must be cleaved to inhibit thrombus growth, 13,14 but the role of proteolysis in the fluid phase has not been established. Therefore, the cleavage of VWF by ADAMTS13 was assessed in a cone-plate viscometer to minimize the contribution of surface interactions. The results indicate that proteolysis of fluid phase VWF-platelet complexes is likely to determine the steady state size distribution of circulating VWF multimers in vivo. Methods Recombinant ADAMTS13Full-length human ADAMTS13 with a C-terminal V5 tag was expressed in TRex 293 cells (Invitrogen) as described previously 15 and partially purified by anion exchange chromatography. In brief, conditioned medium containing recombinant ADAMTS13 was supplemented with proteinase inhibitors (0.1 mol/L D-Phe-Pro-Arg-chloromethane and 144 mol/L phenylmethylsulfonyl fluoride and applied to tandem columns of HiTrap Q Sepharose (2 ϫ 5 mL; GE Healthcare, Chalfont St Giles, United Kingdom). The columns were washed with 20 mM Tris-HCl, pH 8.0, 100 mM NaCl, and developed with a linear gradient of 0 to 50 mM CaCl 2 in 20 mM Tris-HCl, pH 8.0, and 100 mM NaCl. Fractions containing ADAMTS13 were combined,...

show abstract

Section: Discussionmentioning

confidence: 99%

Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress

Shim

Anderson

Tuley

et al. 2008

Blood

149

144

View full text Add to dashboard Cite

show abstract

“…The bleeding tendency varies widely in different patients and appears broadly related to platelet count. Although it was suggested that the marked platelet macrocytosis of MYH9 ‐RD results in a reduced bleeding tendency and in a higher thromboembolic risk with respect to subjects with the same degree of thrombocytopenia but normal platelet size (McDunn et al , 1991; Goto et al , 1998), there are no convincing data supporting this hypothesis. Bleeding symptoms are represented in most cases by easy bruising, menorrhagia, epistaxis and/or gum bleeding (Noris et al , 1998; Yi et al , 2006; Kunishima et al , 2007; Pecci et al , 2010a).…”

Section: Clinical Picturementioning

confidence: 99%

Recent advances in the understanding and management of MYH9‐related inherited thrombocytopenias

2011

View full text Add to dashboard Cite

MYH9-related disease (MYH9-RD) is one of the most frequent forms of inherited thrombocytopenia. It is transmitted in an autosomal dominant fashion and derives from mutations of MYH9, the gene for the heavy chain of non-muscle myosin IIA. Patients present with congenital macrothrombocytopenia with mild bleeding tendency and may develop kidney dysfunction, deafness and cataracts later in life. The term MYH9-RD encompasses four autosomal-dominant thrombocytopenias that were previously described as distinct disorders, namely May-Hegglin Anomaly, Sebastian, Fechtner and Epstein syndromes. Thrombocytopenia is usually mild and derives from complex defects of megakaryocyte maturation and platelet formation. It is easily diagnosed, in that the presence of giant platelets in peripheral blood raises the suspicion of MYH9-RD and a simple immunofluorescence test on blood films confirms the diagnostic hypothesis. However, genotype/phenotype correlations have been recognized and mutation screening is therefore required to define the risk of acquiring extra-haematological defects. Results of a small clinical study suggested that a non-peptide thrombopoietin mimetic might greatly benefit both thrombocytopenia and bleeding tendency of MYH9-RD patients

show abstract

“…Indeed MYH9-RD does not necessarily protect against cardiovascular diseases and thromboses despite reduced platelet number as observed in a few patients. [17][18][19] Thus, agents that increase platelet count may indeed be considered with caution. To evaluate this possibility, histology on various tissues were performed to check for the presence of microthrombi.…”

mentioning

confidence: 99%

Romiplostim administration shows reduced megakaryocyte response-capacity and increased myelofibrosis in a mouse model of MYH9-RD

Léon

Evert²,

Dombrowski³

et al. 2012

Blood

View full text Add to dashboard Cite

Macrothrombocytopenia in MYH9-related disease (MYH9-RD) results from defects in nonmuscular myosin-IIA function. Thrombopoietin receptor agonists (eltrombopag; romiplostim) seem to improve hemostasis, but little is known about their biologic effects in MYH9-RD. We administered romiplostim to Myh9 ؊/؊ mice (100 g/kg, every 3 days, during 1 month). MKs increased to similar numbers in Myh9 ؊/؊ and wild-type (WT) mice (with an increase in immature MKs), but Myh9 ؊/؊ platelet count response was much less (2.5-fold vs 8-fold increase). A strong increase in MK nuclei emboli in the lung, in WT and Myh9 ؊/؊ mice, indicates increased transmigration of MKs from the BM. Prolonged (but not acute) treatment with romiplostim decreased expression of GPIb-IX-V complex and GPVI, but not of GPIIbIIIa, and bleeding time increased in WT mice. Microcirculation was not altered by the increased number of large platelets in any of the assessed organs, but in Myh9 ؊/؊ mice a much stronger increase in BM reticulin fibers was present after 4 weeks of romiplostim treatment vs WT mice. These data further encourage short-term use of thrombopoietic agents in patients with MYH9-RDs; however, myelofibrosis has to be considered as a potential severe adverse effect during longer treatment. Reduction of GPIbIX/GPVI expression by romiplostim requires further studies. IntroductionMYH9-related disorders (MYH9-RDs) are a group of rare diseases characterized by congenital macrothrombocytopenia that results from mutations in the MYH9 gene encoding the nonmuscle myosin IIA, the only isoform of myosin present in platelets. 1 Thrombocytopenia ranges from mild to severe and remains relatively stable in a person throughout life. Patients may experience easy bruising, epistaxis, and menorrhagia, in some rare occasions requiring blood transfusion. Other manifestations may occur later in life such as cataract, hearing loss, and nephropathy; the mechanism leading to these additional symptoms is presently unknown. 2,3 In these patients, thrombocytopenia results from defective platelet production, probably resulting from impairment in marrow MK maturation because of decreased or abnormal myosin IIA, leading to a strong decrease in their capacity to extend proplatelets. 4,5 Second-generation thrombopoietic agents, which stimulate megakaryocytopoiesis by binding to the thrombopoietin (TPO) receptor, 6 may be an option for increasing the platelet count in MYH9-RDs. Two of these TPO receptor agonists have completed phase 3 trials in primary immune thrombocytopenia (eltrombopag, a nonpeptide TPO receptor agonist, and romiplostim, a peptide TPO receptor agonist 7,8 ) and have been recently approved in several countries for treatment of certain patients with immune thrombocytopenia.Eltrombopag administration has recently been tested in patients with MYH9-RDs in a phase 2, multicenter trial, showing moderate increase in platelet counts and reduction in bleeding tendency, 9 suggesting that these new thrombopoietic agents could also represent an interesting therapeutic opti...

show abstract

Functional compensation of the low platelet count by increased individual platelet size in a patient with May-Hegglin anomaly presenting with acute myocardial infarction

Cited by 16 publications

References 15 publications

Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress

Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress

Recent advances in the understanding and management of MYH9‐related inherited thrombocytopenias

Romiplostim administration shows reduced megakaryocyte response-capacity and increased myelofibrosis in a mouse model of MYH9-RD

Contact Info

Product

Resources

About