Fatal Pulmonary Embolus in Congenital Fibrinopenia:Report of Two Cases

Ingram, G. I. C.; McBrien, Dianne; Spencer, H

doi:10.1159/000209109

Cited by 41 publications

(25 citation statements)

References 5 publications

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“…26,27 At this stage, no naturally occurring TSSC6-deficient patients have been reported to test the possibility that spontaneous bleeding problems are encountered due to the reduced inability to form stable platelet plugs at site(s) of injury.…”

Section: Discussionmentioning

confidence: 99%

Impaired “outside-in” integrin αIIbβ3 signaling and thrombus stability in TSSC6-deficient mice

Goschnick

Lau

Wee

et al. 2006

Blood

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We investigated the role of the hematopoietic-specific tetraspanin superfamily member, TSSC6, in platelet function using wild-type mice and TSSC6-deficient mice. TSSC6 is expressed on the surface of murine platelets and is up-regulated by thrombin stimulation, indicating an intracellular pool of TSSC6. Immunoprecipitation/Western blot studies reveal a constitutive physical association of TSSC6 with the integrin ␣ IIb ␤ 3 complex under strong detergent conditions. In vivo evaluation of hemostasis by tail bleeding revealed increased bleeding time, volume of blood lost, and evidence of tail rebleeds in TSSC6 null mice, indicating unstable hemostasis. Using ex vivo techniques, we showed that TSSC6-deficient platelets exhibited impaired kinetics of clot retraction, platelet aggregation at lower doses of PAR-4, and collagen and platelet spreading on fibrinogen in the presence of normal integrin ␣ IIb ␤ 3 expression. TSSC6-deficient platelets showed normal alpha granule secretion, normal "insideout" integrin ␣ IIb ␤ 3 signaling (fluorescein isothiocyanate [FITC]-fibrinogen and JON/A binding), and normal platelet adhesion on fibrinogen. Furthermore, we show that absence of platelet TSSC6 affects the secondary stability of arterial thrombi in vivo upon vascular injury. These data demonstrate that TSSC6 appears to regulate integrin ␣ IIb ␤ 3 "outside-in" signaling events in platelets and is necessary for stability of arterial thrombi in vivo. (Blood.

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Section: Discussionmentioning

confidence: 99%

Impaired “outside-in” integrin αIIbβ3 signaling and thrombus stability in TSSC6-deficient mice

Goschnick

Lau

Wee

et al. 2006

Blood

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“…10,34 A large number of emboli were formed in both the Fg -/-10 and Fg␥⌬5 mice. While available platelet ligands in Fg␥⌬5 mice were sufficient for anchoring thrombi to the vessel wall, the specific ␥ chain C-terminal ␣IIb␤3 binding site was necessary for preventing the splitting of newly formed bonds between platelets within thrombi.…”

Section: Thrombus Stabilization By the Fibrinogen ␥ Chainmentioning

confidence: 99%

Control of thrombus embolization and fibronectin internalization by integrin αIIbβ3 engagement of the fibrinogen γ chain

Papalia

Degen

et al. 2003

Blood

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Fibrin(ogen) deficiency (Fg -/-) was shown previously to be compatible with rapid thrombus growth within injured arterioles, but platelet fibronectin content was increased and newly formed thrombi were unstable. To further define the role of fibrin(ogen) in thrombus formation and stabilization, platelet biology was examined in mice expressing a form of fibrinogen that clots normally but lacks the ␥ chain C-terminal binding site for ␣IIb␤3 (Fg␥⌬5). Thrombus growth within the arterioles of Fg␥⌬5 mice appeared faster than in wild-type mice despite a far greater emboli formation. Unlike Fg -/-mice, the emboli were relatively small and released from the top of thrombi, rather than by fracture at the vessel wall. The fibronectin content in Fg␥⌬5 platelets was also dramatically increased through a ␤3 integrindependent mechanism. The following has been concluded: (1) Fibrin formation contributes to, but is not sufficient for, the stabilization of arterial thrombi. Platelet receptor engagement of the C-terminal of the Fg ␥ chain contributes to the stable incorporation of platelets into thrombi. IntroductionArrest of bleeding at the site of injury is mediated by the adhesion and aggregation of platelets and the formation of the polymerized fibrin matrix. The same general process contributes to the generation of inopportune thrombi within atherosclerotic arteries. Thrombosis in coronary or cerebral arteries is a major cause of morbidity and mortality worldwide. It has been demonstrated that platelet membrane glycoprotein (GP) Ib complex and its ligand, von Willebrand factor (VWF), are involved in initiating platelet adhesion, particularly at high shear. 1 Subsequent stable platelet adhesion and aggregation are mediated by several integrin receptors and their ligands, such as ␣2␤1/collagen and ␣IIb␤3/fibrinogen (Fg) or VWF. 1,2 The GPIb complex is also involved in platelet aggregation. [3][4][5] In contrast to static or low shear conditions, where fibrinogen is necessary for platelet aggregation, 6,7 at high shear efficient platelet aggregation can occur independently of Fg 8-10 and even independently of both VWF and Fg. 10 Under these conditions, fibronectin (Fn) 11 and perhaps other molecules are able to support platelet aggregation. However, fibrinogen and the local conversion of fibrinogen to fibrin by thrombin are generally thought to be indispensable in stabilizing the thrombus. 9,10 Fibrinogen is a 340-kDa glycoprotein dimer consisting of 2 sets of 3 polypeptide chains, termed the A␣, B␤, and ␥ chains. Fibrinogen both provides the fundamental building block for assembly of provisional fibrin matrices and supports cell adhesion through specific integrin and nonintegrin receptor binding motifs. The C-terminal of the ␥ chain contains a critical binding site for the platelet integrin receptor, ␣IIb␤3 (GPIIbIIIa), which has been demonstrated to be required for platelet aggregation. 12,13 Fg from Fg␥⌬5 mice, carrying the genetically modified form of the ␥ chain gene, which eliminates the last 5 residues (QAGDV) of the ␥ ...

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“…Similar findings have been reported in other afibrinogenemic patients. 8,9 Hypercoagulability may be induced by an excess of coagulation factors (factor VIII, von Willebrand factor) due to the infusion of cryoprecipitate or by contamination of the cryoprecipitate with activated coagulation factors. 8,10 The continued use of an oral contraceptive may have played a part in this patient; this drug was not stopped to prevent recurrence of ovulation bleeding.…”

Section: Treatmentmentioning

confidence: 99%

Recurrent Spontaneous Intracerebral Hemorrhage in a Congenitally Afibrinogenemic Patient

Henselmans¹,

Meijer²,

Haaxma³

et al. 1999

Stroke

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Background —Coagulation disorders can cause intracerebral bleeding that may be difficult to detect since subsequent aberrant clot formation may mask early detection. This is an important pitfall because, when diagnosed early, bleeding in these patients is treatable. Case Description —A patient with congenital afibrinogenemia presented with recurrent hemiparesis. Spontaneous intracerebral hemorrhage was diagnosed, despite an initial negative CT scan. Diagnosis, therapy, and complications of therapy are discussed. Conclusions —Intracerebral hemorrhage must be strongly suspected in any patient with a coagulation disorder presenting with matching clinical symptoms. Therapy must be installed immediately, before additional investigations, and should be continued even when initial neuroimaging is negative.

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Fatal Pulmonary Embolus in Congenital Fibrinopenia:Report of Two Cases

Cited by 41 publications

References 5 publications

Impaired “outside-in” integrin αIIbβ3 signaling and thrombus stability in TSSC6-deficient mice

Impaired “outside-in” integrin αIIbβ3 signaling and thrombus stability in TSSC6-deficient mice

Control of thrombus embolization and fibronectin internalization by integrin αIIbβ3 engagement of the fibrinogen γ chain

Recurrent Spontaneous Intracerebral Hemorrhage in a Congenitally Afibrinogenemic Patient

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