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PubMed2004

CEACAM1 enhances invasion and migration of melanocytic and melanoma cells.

Expression of the cell adhesion molecule CEACAM1 in melanomas is an independent factor for the risk of metastasis with a predictive value superior to that of tumor thickness. We have previously shown that CEACAM1 co-localizes at the tumor-stroma interface of invading melanoma masses with integrin beta(3) and that these two adhesion molecules interact via the CEACAM1 cytoplasmic domain. To address the functional consequences of CEACAM1 expression, we investigated invasion and migration of melanocytic and melanoma cells that stably express CEACAM1 using two different in vitro systems. Here, we demonstrate that CEACAM1 expression markedly enhances cell invasion and migration. The enhanced invasion and migration of CEACAM1-transfected cells was dependent on the presence of Tyr-488 within the full-length cytoplasmic CEACAM1 domain. Treatment with anti-CEACAM monoclonal antibodies blocked CEACAM1-enhanced cell invasion and cell migration in a dose-dependent manner. Furthermore, the enhanced invasion and migration of CEACAM1-transfected melanoma cells was blocked by integrin-antagonizing RGD peptides. Expression of integrin beta(3) induces the up-regulation of CEACAM1 in melanocytic MEL6 cells. These results strengthen the view that CEACAM1 and alpha(v)beta(3) integrin are functionally interconnected with respect to the invasive growth of melanomas.

Antibodies, Monoclonal↗
PubMed2003

HoxD3 accelerates wound healing in diabetic mice.

Poorly healing diabetic wounds are characterized by diminished collagen production and impaired angiogenesis. HoxD3, a homeobox transcription factor that promotes angiogenesis and collagen synthesis, is up-regulated during normal wound repair whereas its expression is diminished in poorly healing wounds of the genetically diabetic (db/db) mouse. To determine whether restoring expression of HoxD3 would accelerate diabetic wound healing, we devised a novel method of gene transfer, which incorporates HoxD3 plasmid DNA into a methylcellulose film that is placed on wounds created on db/db mice. The HoxD3 transgene was expressed in endothelial cells, fibroblasts, and keratinocytes of the wounds for up to 10 days. More importantly, a single application of HoxD3 to db/db mice resulted in a statistically significant acceleration of wound closure compared to control-treated wounds. Furthermore, we also observed that the HoxD3-mediated improvement in diabetic wound repair was accompanied by increases in mRNA expression of the HoxD3 target genes, Col1A1 and beta 3-integrin leading to enhanced angiogenesis and collagen deposition in the wounds. Although HoxD3-treated wounds also show improved re-epithelialization as compared to control db/db wounds, this effect was not due to direct stimulation of keratinocyte migration by HoxD3. Finally, we show that despite the dramatic increase in collagen synthesis and deposition in HoxD3-treated wounds, these wounds showed normal remodeling and we found no evidence of abnormal wound healing. These results indicate that HoxD3 may provide a means to directly improve collagen deposition, angiogenesis and closure in poorly healing diabetic wounds.

Animals↗
PubMed2001

Platelet PlA2 polymorphism enhances risk of neurocognitive decline after cardiopulmonary bypass. Multicenter Study of Perioperative Ischemia (McSPI) Research Group.

BACKGROUND: Neurocognitive decline, often produced by atherosclerotic plaque embolization, remains a frequent complication of cardiopulmonary bypass. Plaque fragments may initiate local thrombosis, which, in turn, aggravates the embolic insult. Prothrombotic genetic factors may exacerbate this process. We investigated whether the PlA2 polymorphism of platelet GPIIIa, a prothrombotic risk factor in other cardiovascular settings, is associated with early neurocognitive decline after cardiopulmonary bypass. METHODS: Neurocognitive changes were evaluated by the Mini-Mental State Examination administered preoperatively and on postoperative day 4 and the PlA genotype determined in 70 patients undergoing cardiopulmonary bypass. RESULTS: Forty-nine patients were PlA1/A1, and 21 were PlA1/A2 or PlA2/A2. Fifty-two patients (74%) demonstrated post-cardiopulmonary bypass neurocognitive decline, of which 34 were PlA1/A1 and 18 were PlA1/A2 or PlA2/A2 Multivariate analysis revealed that the PlA2 genotype and baseline Mini-Mental State Examination were significantly associated with greater neurocognitive decline (decreased Mini-Mental State Examination scores, p = 0.036 and 0.024, respectively). CONCLUSIONS: This study demonstrates a link between the PlA2 allele of platelet GPIIIa and more severe neurocognitive decline after cardiopulmonary bypass. Although the mechanism is unknown, it could represent exacerbation of platelet-dependent thrombotic processes associated with plaque embolism.

Aged↗
PubMed1998

The platelet thrombin receptor and postoperative bleeding.

BACKGROUND: We hypothesized that small amounts of thrombin desensitize the platelet thrombin receptor during cardiopulmonary bypass (CPB), resulting in postoperative platelet dysfunction and bleeding. METHODS: Seventy-nine patients were entered into a study designed to measure changes in platelet thrombin receptor function during CPB and to correlate them to postoperative bleeding. In addition to measurements of clinical blood loss, platelet function tests of aggregation, activation, and cell-cell adhesion were used. The thrombin receptor agonist peptide (TRAP) was used to activate the platelets. Flow cytometry was used to measure various platelet surface markers and platelet-white cell interactions during CPB. RESULTS: Compared with preoperative values, both aggregometry and flow cytometry measured a significant reduction of TRAP-induced activation immediately and up to 24 hours after CPB. The response of other activating agents returned to normal by 24 hours. Postoperatively, 8 of 79 patients required excessive blood transfusion (> or = 10 units of blood products) and had significantly decreased TRAP-induced aggregation response. CONCLUSIONS: Our results show that (1) platelet activation, aggregation, and adhesion to leukocytes induced by TRAP are reduced after CPB, (2) decreased thrombin receptor responsiveness is associated with excessive postoperative blood loss, and (3) because the aggregation and activation responses are different for TRAP and thrombin, there may be a second thrombin receptor on platelets that is protected from damage during CPB. These results imply that prevention of the CPB-induced effects on the thrombin receptor will lessen postoperative morbidity associated with blood transfusion.

Blood Loss, Surgical↗
PubMed2003

Chitosan enhances platelet adhesion and aggregation.

In this study, chitosan (MW=50,000) was tested for its enhancing platelet activity in rabbit platelet suspensions and the possible mechanisms involved were further investigated. Our results showed that after initial (5 min) and long-term (30 min) contact of platelets with chitosan, the platelet adhesion to chitosan-coated microtiter plates was dose-dependently increased compared to that of solvent control. Similarly, chitosan also dose-dependently increased the platelet aggregation and the intracellular free Ca(2+) rise of Fura-2-AM loaded platelets. Additionally, in the presence of FITC-labeled anti-CD41/CD61, chitosan significantly enhanced the expression of platelet glycoprotein IIb/IIIa complex assayed by a flow cytometer. It is concluded that chitosan is an effective inducer for platelet adhesion and aggregation and the mechanisms of action of chitosan may be associated, at least partly, with the increasing [Ca(2+)](i) mobilization and enhancing expression of GPIIb/IIIa complex on platelet membrane surfaces.

Animals↗
PubMed1997

Hydrodynamic effects and receptor interactions of platelets and their aggregates in linear shear flow.

We have modeled platelet aggregation in a linear shear flow by accounting for two body collision hydrodynamics, platelet activation and receptor biology. Considering platelets and their aggregates as unequal-sized spheres with DLVO interactions (psi(platelet) = -15 mV, Hamaker constant = 10(-19) J), detailed hydrodynamics provided the flow field around the colliding platelets. Trajectory calculations were performed to obtain the far upstream cross-sectional area and the particle flux through this area provided the collision frequency. Only a fraction of platelets brought together by a shearing fluid flow were held together if successfully bound by fibrinogen cross-bridging GPIIb/IIIa receptors on the platelet surfaces. This fraction was calculated by modeling receptor-mediated aggregation using the formalism of Bell (Bell, G. I. 1979. A theoretical model for adhesion between cells mediated by multivalent ligands. Cell Biophys. 1:133-147) where the forward rate of bond formation dictated aggregation during collision and was estimated from the diffusional limited rate of lateral association of receptors multiplied by an effectiveness factor, eta, to give an apparent rate. For a value of eta = 0.0178, we calculated the overall efficiency (including both receptor binding and hydrodynamics effects) for equal-sized platelets with 50,000 receptors/platelet to be 0.206 for G = 41.9 s(-1), 0.05 for G = 335 s(-1), and 0.0086 for G = 1920 s(-1), values which are in agreement with efficiencies determined from initial platelet singlet consumption rates in flow through a tube. From our analysis, we predict that bond formation proceeds at a rate of approximately 0.1925 bonds/microm2 per ms, which is approximately 50-fold slower than the diffusion limited rate of association. This value of eta is also consistent with a colloidal stability of unactivated platelets at low shear rates. Fibrinogen was calculated to mediate aggregation quite efficiently at low shear rates but not at high shear rates. Although secondary collisions (an orbitlike trajectory) form only a small fraction of the total number of collisions, they become important at high shear rates (>750 s(-1)), as these are the only collisions that provide enough time to result in successful aggregate formation mediated by fibrinogen. The overall method provides a hydrodynamic and receptor correction of the Smoluchowski collision kernel and gives a first estimate of eta for the fibrinogen-GPIIb/IIIa cross-bridging of platelets. We also predict that secondary collisions extend the shear rate range at which fibrinogen can mediate successful aggregation.

Adenosine Diphosphate↗
PubMed2002

Antagonists of platelet fibrinogen receptor are less effective in carriers of Pl(A2) polymorphism of beta(3) integrin.

The polymorphism Leu(33)-->Pro (platelet-specific antigen; Pl(A1/A2)) of platelet GPIIIa is a potential risk factor for arterial thrombosis. However, its influence on platelet function remains controversial and little is known about its impact on platelet sensitivity to GPIIb-IIIa antagonists. Our objective was to compare the effectiveness of various GPIIb-IIIa antagonists in Pl(A2)(+) and Pl(A2)(-) carriers. Platelet aggregation was monitored in healthy donors including Pl(A2)(-) (N=31) and Pl(A2)(+) subjects (N=27; 23 Pl(A1/A2), 4 Pl(A2)/(A2)) using the impedance and turbidimetric aggregation techniques. We evaluated the inhibition of ADP- and collagen-induced aggregation by disintegrins, kistrin and echistatin, and the low-molecular-weight blockers, GR144053F ((4-[4-[4-(aminoiminomethyl]-1-piperazinyl]-1-piperidineacetic acid, hydrochloride trihydrate) and eptifibatide (N(6)-(aminoiminomethyl)-N(2)-(3-mercapto-1-oxopropyl-L-lysylglycyl-L-alpha-aspartyl-L-tryptophyl-L-propyl-L-cysteinamide, cyclic (1-->6)-disulfide). Kistrin (10-30 nmol/l) inhibited ADP- and collagen-induced aggregation stronger in Pl(A2)(-) donors than in Pl(A2)(+) donors; there was a significant difference between 50% inhibitory concentrations (IC(50)). The same tendency occurred with moderate concentrations of eptifibatide (40-100 nmol/l) and also at low concentrations of GR144053F (5-10 nmol/l) and high concentrations of echistatin (80-150 nmol/l), although in the case of the two latter inhibitors, the estimated IC(50) values were not significantly different. In conclusion, GPIIb-IIIa blockers representing various classes are less effective inhibitors of platelet aggregation in Pl(A2)(+) carriers; however, the effect of the genotype is both agonist- and antagonist-dependent.

Adult↗
PubMed2003

Syndecan-1-mediated cell spreading requires signaling by alphavbeta3 integrins in human breast carcinoma cells.

Syndecans are cell surface heparan sulfate proteoglycans with regulatory roles in cell adhesion, proliferation, and differentiation [Annu. Rev. Biochem. 68 (1999) 729]. While the syndecan heparan sulfate chains are essential for matrix binding, less is known about the signaling role of their core proteins. To mimic syndecan-specific adhesion, MDA-MB-231 mammary carcinoma cells were plated on antibodies against syndecan-4 or syndecan-1. While cells adherent via syndecan-4 spread, cells adherent via syndecan-1 do not. However, cells adherent via syndecan-1 can be induced to spread by Mn(2+), suggesting that activation of a beta(1) or beta(3) integrin partner is required. Surprisingly, pretreatment of cells with a function-activating beta(1) antibody does not induce spreading, whereas function-blocking beta(1) integrin antibodies do, suggesting involvement of a beta(1)-to-beta(3) integrin cross-talk. Indeed, blockade of beta(1) integrin activation induces alpha(v)beta(3) integrin activation detectable by soluble fibrinogen binding. Spreading in response to syndecan-1 is independent of integrin-ligand binding. Furthermore, competition with soluble murine syndecan-1 ectodomain, which does not disrupt cell adhesion, nonetheless blocks the spreading mechanism. These data suggest that the ectodomain of the syndecan-1 core protein directly participates in the formation of a signaling complex that signals in cooperation with alpha(v)beta(3) integrins; signaling via this complex is negatively regulated by beta(1) integrins.

Breast Neoplasms↗
PubMed2003

The C-terminal peptide of thrombospondin-1 stimulates distinct signaling pathways but induces an activation-independent agglutination of platelets and other cells.

A peptide from the C-terminal domain of thrombospondin-1 (4N1-1) has been proposed to stimulate platelet aggregation by a novel mechanism involving both an activation-independent agglutination and an activation-dependent, glycoprotein (GP) IIb/IIIa-mediated aggregation which involves GPVI signaling but does not involve CD47. The present study demonstrates that 4N1-1 stimulated a different pattern of signal transduction pathways than the GPVI agonist convulxin. Furthermore, 4N1-1-induced platelet aggregation was activation-independent and not dependent on GPVI or GPIIb/IIIa. Interestingly, 4N1-1 also stimulated activation-independent agglutination of different megakaryocytic and non-megakaryocytic cells. 4N1-1-induced cell agglutination but not platelet signaling was inhibited by anti-CD47 antibodies.

Antigens, CD↗
PubMed1998

Thrombin induces the association of cyclic ADP-ribose-synthesizing CD38 with the platelet cytoskeleton.

The effect of platelet stimulation on the subcellular localization of CD38, a membrane glycoprotein that catalyses the synthesis of cyclic ADP-ribose from beta-NAD+ was investigated. Treatment of human platelets with thrombin caused the association of about 40% of the total ADP-ribosyl cyclase activity with the cytoskeleton, through the translocation of the CD38 molecule from the Triton X-100-soluble to the insoluble fraction. The interaction of CD38 with the cytoskeleton was a specific and reversible process, mediated by the binding to the actin-rich filaments and was inhibited by treatment of platelets with cytochalasin D. This event was regulated by integrin alphaIIb beta3 and platelet aggregation as it was prevented by the inhibition of fibrinogen binding and was not observed in platelets from a patient affected by Glanzmann thrombasthenia. These results demonstrate that the subcellular localization of CD38 can be influenced by platelet stimulation with physiological agonists, and that membrane CD38 can interact with intracellular proteins.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Nucleotide sequence of a cDNA encoding a common precursor of disintegrin flavostatin and hemorrhagic factor HR2a from the venom of Trimeresurus flavoviridis.

The venom of Trimeresurus flavoviridis has three disintegrins that act as platelet aggregation inhibitors by binding to integrin alphaIIb beta3 on platelets through its Arg-Gly-Asp sequence. We isolated the cDNA encoding the flavostatin precursor that is one of the disintegrins in T. flavoviridis venom. The open reading frame consisted of four regions, a pre-peptide region, a metalloprotease region, a spacer region and a disintegrin region, indicating that the flavostatin precursor belongs to the metalloprotease/disintegrin family. Surprisingly, the deduced amino acid sequence of the metalloprotease region was completely consistent with that of hemorrhagic metalloprotease HR2a, which indicated that this metalloprotease released from the flavostatin precursor functions as a hemorrhagic factor. These observations indicated that a disintegrin and a hemorrhagic metalloprotease were synthesized as a common precursor. Thus, our results support the hypothesis that a disintegrin is synthesized as a metalloprotease/disintegrin precursor and matures by cleavage from the precursor molecule.

Amino Acid Sequence↗
PubMed2001

Differential expression of integrin alpha v and beta 3 in serosal tissue of human intraperitoneal organs and adhesion.

OBJECTIVE: To assess the expression of integrin alpha v and beta 3 in the serosal tissue of intraperitoneal organs and adhesions in persons with and without adhesions. DESIGN: Prospective study. SETTING: Academic research centers. PATIENT(S): Fifty-seven patients undergoing abdominal or pelvic surgery. MAIN OUTCOME MEASURE(S): Integrin alpha v and beta 3 messenger RNA (mRNA) expression was evaluated by quantitative reverse transcription polymerase chain reaction. RESULT(S): The serosal tissue of the parietal peritoneum, uterus, fallopian tubes, ovary, and the large and small bowel, as well as peritoneal adhesions, skin, fascia, subcutaneous tissue, and omentum, expresses integrin alpha v and beta 3 mRNA. The level of alpha v and beta 3 mRNA expression varied among these tissues; expression of the former substance was highest in uterine serosa and lowest in the skin and small bowel, and expression of the latter substance was highest in the fallopian tubes and skin and lowest in the uterine serosa. Parietal peritoneum and adhesions express equal levels of integrin alpha v; however, integrin beta 3 expression was >100-fold lower in adhesions than in peritoneum. The level of integrin beta 3 expression in omentum, small and large bowels, and subcutaneous tissue was 100-fold to 10,000-fold lower than in other tissues. CONCLUSION(S): Serosal tissue of peritoneal organs and adhesions express variable levels of integrin alpha v and beta 3 mRNA. On the basis of such variation and the knowledge that tissue injury alters local integrin expression, integrins may play a key role in adhesion development, particularly in tissue with higher integrin expression.

Adult↗
PubMed2003

Combined thrombophilic polymorphisms in women with idiopathic recurrent miscarriage.

OBJECTIVE: To identify associations or interrelations between carriage of the methylenetetrahydrofolate reductase (MTHFR) C677T, the MTHFR A1298C, the factor V Leiden G1691A, the factor II prothrombin G20210A, the human platelet antigen (HPA) 1 C12548T, and the apolipoprotein (APO) B R3500Q polymorphisms and idiopathic recurrent miscarriage (IRM). DESIGN: Prospective case control study. SETTING: Academic research institution. PATIENT(S): One hundred forty-five women with a history of three or more consecutive pregnancy losses before 20 weeks gestation and 101 healthy postmenopausal women with at least two live births and no history of pregnancy loss. INTERVENTION(S): Peripheral venous punctures. MAIN OUTCOME MEASURE(S): Multiplex polymerase chain reaction was performed to identify the different alleles of six candidate genetic risk factors for IRM (MTHFR C677T, MTHFR A1298C, factor V Leiden G1691A, factor II prothrombin G20210A, HPA 1 C12548T, and the APO B R3500Q). RESULT(S): Allele and genotype frequencies of all polymorphisms were not significantly different between the study and the control groups. Also, no significant associations occurred between combinations of polymorphisms and the occurrence of IRM. CONCLUSION(S): Our data fall short of showing any significant association between single polymorphisms of the MTHFR, the Factor V Leiden, the Factor II Prothrombin, the HPA 1 and APO B genes or combinations of these polymorphisms and the occurrence of IRM.

Abortion, Habitual↗
PubMed2001

Simultaneous flow cytometric measurement of K-562 megakaryocytic differentiation and CD56+ large granular lymphocyte cytotoxicity.

K-562 cells have the capacity to undergo multi-lineage differentiation, which may be crucial to their ability to serve as target reservoirs for CD56+ large granular lymphocytes (LGL). Conventional techniques using chromium release assays to measure lymphocyte-mediated cytotoxicity suffer from disadvantages, including radioactive contamination and the inability to simultaneously determine K-562 and/or CD56+ lymphocyte phenotypes. We illustrate here a three-color flow cytometric method providing for the simultaneous evaluation of K-562-CD56+ LGL binding, K-562 cell viability, and the status of K-562 cell differentiation. Phorbol 12-myristate 13-acetate (PMA) engenders megakaryocytic differentiation in K-562 cell populations, as measured by presentation of the beta(3) integrin (gpIIIa, CD61), while maintaining a negative expression of MHC-I and MHC-II molecules. Using the auto-fluorescence of K-562 cells, flow cytometry can be used to demonstrate a significant decrease in CD56+ LGL activity against K-562 cells in populations pre-incubated with PMA. The capacity of three-color flow cytometry to measure lymphocyte-target cell binding and cell death kinetics, while simultaneously determining target cell phenotype, permits the specific localization of CD61-expressing K-562 cells to areas inconsistent with CD56+ LGL-mediated patterns of lysis.

Antigens, CD↗
PubMed2004

Young male smokers have altered platelets and endothelium that precedes atherosclerosis.

BACKGROUND: Cigarette smoking results in abnormalities of platelets and endothelium with platelet dysfunction implicated in vascular complications. Healthy endothelium plays a pivotal role in regulating hemostasis via the inhibition of platelet activation and aggregation. Thus, we examined if platelet dysfunction correlated with serum vWF levels-a circulating marker of endothelial dysfunction. MATERIALS AND METHODS: We tested this hypothesis in young male smokers. The parameters of platelet function tested included: CD62/CD63; Glycoprotein (GP) IIb/IIIa; Platelet function analzyer (PFA) studies, platelet aggregometry, flow assessment of platelet microparticles, platelet-leukocyte interactions and receptor numbers. Endothelial dysfunction was assessed with serum von Willebrand Factor (vWF). RESULTS: There was a significant increase in platelet CD62 receptor expression and aggregation with an associated delay in time to aggregation using PFA. Endothelial dysfunction was represented by higher serum levels of von Willebrand Factor. All other platelet parameters tested were within the standardized reference range. CONCLUSIONS: These initial data suggests that anti-platelet therapy may have a role in reduction of platelet activation and aggregation in young smokers and possibly alter vascular endothelial abnormalities.

Adenosine Diphosphate↗
PubMed2003

Relationship between the expression levels of CD61, CD63, and PAC-1 on platelet surface in peripheral blood and the transplanted kidney function.

OBJECTIVE: To analyze the relationships between the expression levels of CD61, CD63, and PAC-1 on the platelet surface and the incidences of acute rejection and tubular necrosis as well as the recovery of graft function after renal transplantation. METHODS: The expression levels of CD61, CD63, and PAC-1 on platelet surfaces were assayed by flow cytometry in 86 patients with different stages of uremia before and after transplantation. Patients were divided into three groups: 29 patients with normal graft function, 30 with acute rejection, and 27 with acute tubular necrosis. Patients with acute rejection were randomly assigned into groups treated with or without anticoagulants. RESULTS: The expression levels of CD61, CD63, and PAC-1 on platelet surfaces significantly increased (P <.05) among patients with acute rejection, as compared with those with normal graft function or acute tubular necrosis. Compared with controls, the expression levels of CD61, CD63, and PAC-1 were lower among acute rejection patients who, received anticoagulant therapy. The recovery time for graft function shorter and, the 1-year patients and graft survival rates higher. CONCLUSIONS: The pretransplant expression levels of CD61, CD63, and PAC-1 on platelet surface were significantly higher among patients with acute rejection, suggesting that this complication rather than acute tubular necrosis may be related to platelet activation. Patients with acute rejection displayed benefit from anticoagulant therapy.

Adult↗
PubMed2003

Platelets and capillary injury in acute humoral rejection of renal allografts.

Platelet accumulation in glomerular capillaries (GC) and peritubular capillaries (PC) has pathogenetic importance in antibody-mediated hyperacute renal allograft rejection. CD61 is expressed constitutively by platelets, by platelet microparticles arising from platelet activation, and is readily detectable by immunohistochemistry. This study examined the immunohistochemical localization of CD61 in acute humoral rejection (AHR) of renal allografts to explore the relationship of platelet accumulation to antibody-mediated rejection. Two observers graded the extent of CD61 staining in PC and GC from 0 (none) to 2+ (>50%) in 15 renal allograft biopsy specimens with AHR and compared these with tissues from allografts with acute cellular rejection (ACR) (n = 23); acute calcineurin inhibitor toxicity (ACIT) (n = 21) with thrombotic microangiopathy (TMA) (n = 11) and tubular toxicity only (n = 10); acute tubular necrosis (ATN) (n = 16); acute renal vein thrombosis (RVT) (n = 4); and histologically unremarkable native kidneys (n = 26). Selected tissues were examined by electron microscopy and stained for CD34 by immunohistochemistry. Histologically unremarkable native kidney tissues had CD61 only in scattered small lumenal granules in GC and PC. Mural and occlusive lumenal CD61 deposits (>0.5+) were observed in 13 of 13 (100%) allograft tissues with GC thrombi due to AHR (1) and ACIT TMA (9) and RVT (3). Twenty-seven of 66 allografts (40.9%) without glomerular thrombi had >0.5+ GC CD61 in AHR (60%), ACR (26%), tubular ACIT (60%), and ATN (44%). More than trace (>0.5+) PC mural and lumenal CD61 deposits were seen only in AHR (53.3%) and ACR (30%). PC CD61 correlated with interstitial hemorrhage (r = 0.64), neutrophilic capillaritis (r = 0.47), and interstitial inflammation (r = 0.47) (P <0.001 for each). PC CD61 was observed in 11 of 11 foci of necrosis due to AHR, RVT, and ischemia. In AHR, capillaries with CD61 deposits had few platelets, numerous microvesicles and membrane fragments, severe endothelial injury seen on electron microscopy, and reduced capillary CD34 expression. CD61 detection by immunohistochemistry revealed products of capillary platelet activation in allograft biopsy specimens without light microscopic thrombi. Observations in this study suggest that intracapillary platelet activation occurs in response to graft capillary injury from many causes and may not be specific for antibody-mediated rejection.

Acute Disease↗